Publications by authors named "Jonathan P Godbout"

83 Publications

Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia.

Authors:
Kristina G Witcher Chelsea E Bray Titikorn Chunchai Fangli Zhao Shane M O'Neil Alan J Gordillo Warren A Campbell Daniel B McKim Xiaoyu Liu Julia E Dziabis Ning Quan Daniel S Eiferman Andy J Fischer Olga N Kokiko-Cochran Candice Askwith Jonathan P Godbout

J Neurosci 2021 Feb 15;41(7):1597-1616. Epub 2021 Jan 15.

Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), and chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion injury (FPI) in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To understand the relationship between microglia, neurons, and other glia, single-cell RNA sequencing was completed 7 dpi, a critical time point in the evolution from acute to chronic pathogenesis. Cortical microglia exhibited distinct TBI-associated clustering with increased type-1 interferon and neurodegenerative/damage-related genes. In cortical neurons, genes associated with dopamine signaling, long-term potentiation, calcium signaling, and synaptogenesis were suppressed. Microglial depletion reversed the majority of these neuronal alterations. Furthermore, there was reduced cortical dendritic complexity 7 dpi, reduced neuronal connectively 30 dpi, and cognitive impairment 30 dpi. All of these TBI-associated functional and behavioral impairments were prevented by microglial depletion. Collectively, these studies indicate that microglia promote persistent neuropathology and long-term functional impairments in neuronal homeostasis after TBI. Millions of traumatic brain injuries (TBIs) occur in the United States alone each year. Survivors face elevated rates of cognitive and psychiatric complications long after the inciting injury. Recent studies of human brain injury link chronic neuroinflammation to adverse neurologic outcomes, suggesting that evolving inflammatory processes may be an opportunity for intervention. Here, we eliminate microglia to compare the effects of diffuse TBI on neurons in the presence and absence of microglia and microglia-mediated inflammation. In the absence of microglia, neurons do not undergo TBI-induced changes in gene transcription or structure. Microglial elimination prevented TBI-induced cognitive changes 30 d postinjury (dpi). Therefore, microglia have a critical role in disrupting neuronal homeostasis after TBI, particularly at subacute and chronic timepoints.
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http://dx.doi.org/10.1523/JNEUROSCI.2469-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896020PMC
February 2021

Correction: Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress.

Authors:
Damon J DiSabato Daniel P Nemeth Xiaoyu Liu Kristina G Witcher Shane M O'Neil Braedan Oliver Chelsea E Bray John F Sheridan Jonathan P Godbout Ning Quan

Mol Psychiatry 2020 Jun 30. Epub 2020 Jun 30.

Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41380-020-0833-2DOI Listing
June 2020

Comparison between midline and lateral fluid percussion injury in mice reveals prolonged but divergent cortical neuroinflammation.

Authors:
Kristina G Witcher Julia E Dziabis Chelsea E Bray Alan J Gordillo Julia E Kumar Daniel S Eiferman Jonathan P Godbout Olga N Kokiko-Cochran

Brain Res 2020 11 24;1746:146987. Epub 2020 Jun 24.

Department of Neuroscience, The Ohio State University, 333 W 10(th) Ave, Columbus, OH 43210, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, 460 W 12(th) Ave, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Dr, Columbus, OH 43210, USA. Electronic address:

Animal models are critical for determining the mechanisms mediating traumatic brain injury-induced (TBI) neuropathology. Fluid percussion injury (FPI) is a widely used model of brain injury typically applied either midline or parasagittally (lateral). Midline FPI induces a diffuse TBI, while lateral FPI induces both focal cortical injury (ipsilateral hemisphere) and diffuse injury (contralateral hemisphere). Nonetheless, discrete differences in neuroinflammation and neuropathology between these two versions of FPI remain unclear. The purpose of this study was to compare acute (4-72 h) and subacute (7 days) neuroinflammatory responses between midline and lateral FPI. Midline FPI resulted in longer righting reflex times than lateral FPI. At acute time points, the inflammatory responses to the two different injuries were similar. For instance, there was evidence of monocytes and cytokine mRNA expression in the brain with both injuries acutely. Midline FPI had the highest proportion of brain monocytes and highest IL-1β/TNFα mRNA expression 24 h later. NanoString nCounter analysis 7 days post-injury revealed robust and prolonged expression of inflammatory-related genes in the cortex after midline FPI compared to lateral FPI; however, Iba-1 cortical immunoreactivity was increased with lateral FPI. Thus, midline and lateral FPI caused similar cortical neuroinflammatory responses acutely and mRNA expression of inflammatory genes was detectable in the brain 7 days later. The primary divergence was that inflammatory gene expression was greater and more diverse subacutely after midline FPI. These results provide novel insight to variations between midline and lateral FPI, which may recapitulate unique temporal pathogenesis.
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http://dx.doi.org/10.1016/j.brainres.2020.146987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484082PMC
November 2020

Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress.

Authors:
Damon J DiSabato Daniel P Nemeth Xiaoyu Liu Kristina G Witcher Shane M O'Neil Braedan Oliver Chelsea E Bray John F Sheridan Jonathan P Godbout Ning Quan

Mol Psychiatry 2020 May 22. Epub 2020 May 22.

Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, USA.

Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Stress-induced monocyte trafficking to the brain was also blocked by IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1) abrogated the stress-induced deficits in social interaction and working memory. In addition, viral-mediated selective IL-1R1 deletion in hippocampal neurons confirmed that IL-1 receptor in the hippocampus was critical for stress-induced behavioral deficits. Furthermore, selective restoration of IL-1R1 on glutamatergic neurons was sufficient to reestablish the impairments of social interaction and working memory after stress. RNA-sequencing of the hippocampus revealed that stress increased several canonical pathways (TREM1, NF-κB, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1β, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1. Collectively, stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.
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http://dx.doi.org/10.1038/s41380-020-0788-3DOI Listing
May 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Authors:
Katie A Thies Anisha M Hammer Blake E Hildreth Sarah A Steck Jonathan M Spehar Raleigh D Kladney Jennifer A Geisler Manjusri Das Luke O Russell Jerome F Bey Chelsea M Bolyard Robert Pilarski Anthony J Trimboli Maria C Cuitiño Christopher S Koivisto Daniel G Stover Lynn Schoenfield Jose Otero Jonathan P Godbout Arnab Chakravarti Matthew D Ringel Bhuvaneswari Ramaswamy Zaibo Li Balveen Kaur Gustavo Leone Michael C Ostrowski Steven T Sizemore Gina M Sizemore

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Sleep Disruption Exacerbates and Prolongs the Inflammatory Response to Traumatic Brain Injury.

Authors:
Zoe M Tapp Julia E Kumar Kristina G Witcher Ravitej R Atluri John A Velasquez Shane M O'Neil Julia E Dziabis Chelsea E Bray John F Sheridan Jonathan P Godbout Olga N Kokiko-Cochran

J Neurotrauma 2020 08 21;37(16):1829-1843. Epub 2020 Apr 21.

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

Traumatic brain injury (TBI) alters stress responses, which may influence neuroinflammation and behavioral outcome. Sleep disruption (SD) is an understudied post-injury environmental stressor that directly engages stress-immune pathways. Thus, we predicted that maladaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis after TBI compromise the neuroendocrine response to SD and exacerbate neuroinflammation. To test this, we induced lateral fluid percussion TBI or sham injury in female and male C57BL/6 mice aged 8-10 weeks that were then left undisturbed or exposed to 3 days of transient SD. At 3 days post-injury (DPI) plasma corticosterone (CORT) was reduced in TBI compared with sham mice, indicating altered HPA-mediated stress response to SD. This response was associated with approach-avoid conflict behavior and exaggerated cortical neuroinflammation. Post-injury SD specifically enhanced neutrophil trafficking to the injured brain in conjunction with dysregulated aquaporin-4 (AQP4) polarization. Delayed and persistent effects of post-injury SD were determined 4 days after SD concluded at 7 DPI. SD prolonged anxiety-like behavior regardless of injury and was associated with increased cortical Iba1 labeling in both sham and TBI mice. Strikingly, TBI SD mice displayed an increased number of CD45 cells near the site of injury, enhanced cortical glial fibrillary acidic protein (GFAP) immunolabeling, and persistent expression of and 7 DPI compared with TBI mice. These results support the hypothesis that post-injury SD alters stress-immune pathways and inflammatory outcomes after TBI. These data provide new insight to the dynamic interplay between TBI, stress, and inflammation.
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http://dx.doi.org/10.1089/neu.2020.7010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404833PMC
August 2020

Acute peripheral inflammation and post-traumatic sleep differ between sexes after experimental diffuse brain injury.

Authors:
Maha Saber Katherine R Giordano Yerin Hur John B Ortiz Helena Morrison Jonathan P Godbout Sean M Murphy Jonathan Lifshitz Rachel K Rowe

Eur J Neurosci 2020 07 27;52(1):2791-2814. Epub 2019 Nov 27.

BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA.

Identifying differential responses between sexes following traumatic brain injury (TBI) can elucidate the mechanisms behind disease pathology. Peripheral and central inflammation in the pathophysiology of TBI can increase sleep in male rodents, but this remains untested in females. We hypothesized that diffuse TBI would increase inflammation and sleep in males more so than in females. Diffuse TBI was induced in C57BL/6J mice and serial blood samples were collected (baseline, 1, 5, 7 days post-injury [DPI]) to quantify peripheral immune cell populations and sleep regulatory cytokines. Brains and spleens were harvested at 7DPI to quantify central and peripheral immune cells, respectively. Mixed-effects regression models were used for data analysis. Female TBI mice had 77%-124% higher IL-6 levels than male TBI mice at 1 and 5DPI, whereas IL-1β and TNF-α levels were similar between sexes at all timepoints. Despite baseline sex differences in blood-measured Ly6C monocytes (females had 40% more than males), TBI reduced monocytes by 67% in TBI mice at 1DPI. Male TBI mice had 31%-33% more blood-measured and 31% more spleen-measured Ly6G neutrophils than female TBI mice at 1 and 5DPI, and 7DPI, respectively. Compared with sham, TBI increased sleep in both sexes during the first light and dark cycles. Male TBI mice slept 11%-17% more than female TBI mice, depending on the cycle. Thus, sex and TBI interactions may alter the peripheral inflammation profile and sleep patterns, which might explain discrepancies in disease progression based on sex.
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http://dx.doi.org/10.1111/ejn.14611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195243PMC
July 2020

Interleukin-1 causes CNS inflammatory cytokine expression via endothelia-microglia bi-cellular signaling.

Authors:
Ling Zhu Xiaoyu Liu Daniel P Nemeth Damon J DiSabato Kristina G Witcher Daniel B Mckim Braedan Oliver Xi Le Gowthami Gorantla Olimpia Berdysz Jiaoni Li Aishwarya D Ramani Zhibiao Chen Dongcheng Wu Jonathan P Godbout Ning Quan

Brain Behav Immun 2019 10 19;81:292-304. Epub 2019 Jun 19.

Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL 33458, USA. Electronic address:

As a major producer of the inflammatory cytokine interleukin-1 (IL-1), peripheral macrophages can augment IL-1 expression via type 1 IL-1 receptor (IL-1R1) mediated autocrine self-amplification. In the CNS, microglial cells are the major producers of inflammatory cytokines, but express negligible levels of IL-1R1. In the present study, we showed CNS IL-1 induced microglial proinflammatory cytokine expression was mediated by endothelial, not microglial, IL-1R1. This paracrine mechanism was further dissected in vitro. IL-1 was unable to stimulate inflammatory cytokine expression directly from the microglial cell line BV-2, but it stimulated the brain endothelial cell line bEnd.3 to produce a factor(s) in the culture supernatant, which was capable of inducing inflammatory cytokine expression in BV-2. We termed this factor IL-1-induced microglial activation factors (IMAF). BV-2 cytokine expression was inducible by extracellular ATP, but IL-1 did not stimulate the release of ATP from bEnd.3 cells. Filtration of IMAF by size-exclusion membranes showed IMAF activity resided in molecules larger than 50 kd and incubation of IMAF at 95 °C for 5 min did not alter its activity. Microglial inhibitor minocycline was unable to block IMAF activity, even though it blocked LPS induced cytokine expression in BV-2 cells. Adding NF-κB inhibitor to the bEnd.3 cells abolished IL-1 induced cytokine expression in this bi-cellular system, but adding NF-κB inhibitor after IMAF is already produced failed to abrogate IMAF induced cytokine expression in BV-2 cells. RNA sequencing of IL-1 stimulated endothelial cells revealed increased expression of genes involved in the production and processing of hyaluronic acid (HA), suggesting HA as a candidate of IMAF. Inhibition of hyaluronidase by ascorbyl palmitate (AP) abolished IMAF-induced cytokine expression in BV-2 cells. AP administration in vivo also inhibited ICV IL-1-induced IL-1 expression in the hippocampus and hypothalamus. In vitro, either TLR2 or TLR4 inhibitors blocked IMAF induced BV-2 cytokine expression. In vivo, however, IL-1 induced cytokine expression persisted in either TLR2 or TLR4 knockouts. These results demonstrate IL-1 induced inflammatory cytokine expression in the CNS requires a bi-cellular system and HA could be a candidate for IMAF.
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http://dx.doi.org/10.1016/j.bbi.2019.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754782PMC
October 2019

Mammary tumors compromise time-of-day differences in hypothalamic gene expression and circadian behavior and physiology in mice.

Authors:
Kyle A Sullivan Savannah R Bever Daniel B McKim Jonathan P Godbout John F Sheridan Karl Obrietan Leah M Pyter

Brain Behav Immun 2019 08 17;80:805-817. Epub 2019 May 17.

Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Neuroscience, Ohio State University, Columbus, OH, USA; Departments of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, USA; James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH, USA. Electronic address:

Circadian rhythms influence various aspects of biology, including hormonal, immunological, and behavioral processes. These 24-hour oscillations are necessary to optimize cellular functions and to synchronize these processes with the environment. Breast cancer patients and survivors frequently report disruptions in circadian oscillations that adversely affect quality-of-life, including fragmented sleep-wake cycles and flattened cortisol rhythms, which are associated with negative behavioral comorbidities (e.g., fatigue). However, the potential causal role of tumor biology in circadian dysregulation has not been investigated. Here, we examined the extent to which sham surgery, non-metastatic mammary tumors, or mammary tumor removal in mice disrupts circadian rhythms in brain clock gene expression, locomotor behavior (free-running and entrained), and physiological rhythms that have been associated with cancer behavioral comorbidities. Tumors and tumor resection altered time-of-day differences in hypothalamic expression of eight circadian-regulated genes. The onset of activity in entrained running behavior was advanced in tumor-bearing mice, and the amplitude of free-running rhythms was increased in tumor-resected mice. Tumors flattened rhythms in circulating corticosterone and Ly6c monocytes which were largely restored by surgical tumor resection. This work implies that tumors alone may directly impact central and/or peripheral circadian rhythmicity in breast cancer patients, and that these effects may persist in cancer survivors, potentially contributing to behavioral comorbidities.
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http://dx.doi.org/10.1016/j.bbi.2019.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664435PMC
August 2019

A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI.

Authors:
Zoe M Tapp Jonathan P Godbout Olga N Kokiko-Cochran

Front Neurol 2019 24;10:345. Epub 2019 Apr 24.

Department of Neuroscience, Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH, United States.

Each year approximately 1.7 million people sustain a traumatic brain injury (TBI) in the US alone. Associated with these head injuries is a high prevalence of neuropsychiatric symptoms including irritability, depression, and anxiety. Neuroinflammation, due in part to microglia, can worsen or even cause neuropsychiatric disorders after TBI. For example, mounting evidence demonstrates that microglia become "primed" or hyper-reactive with an exaggerated pro-inflammatory phenotype following multiple immune challenges. Microglial priming occurs after experimental TBI and correlates with the emergence of depressive-like behavior as well as cognitive dysfunction. Critically, immune challenges are various and include illness, aging, and stress. The collective influence of any combination of these immune challenges shapes the neuroimmune environment and the response to TBI. For example, stress reliably induces inflammation and could therefore be a gateway to altered neuropathology and behavioral decline following TBI. Given the increasing incidence of stress-related psychiatric disorders after TBI, the degree in which stress affects outcome is of particular interest. This review aims to highlight the role of the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of stress-immune pathway communication following TBI. We will first describe maladaptive neuroinflammation after TBI and how stress contributes to inflammation through both anti- and pro-inflammatory mechanisms. Clinical and experimental data describing HPA-axis dysfunction and consequences of altered stress responses after TBI will be discussed. Lastly, we will review common stress models used after TBI that could better elucidate the relationship between HPA axis dysfunction and maladaptive inflammation following TBI. Together, the studies described in this review suggest that HPA axis dysfunction after brain injury is prevalent and contributes to the dynamic nature of the neuroinflammatory response to brain injury. Experimental stressors that directly engage the HPA axis represent important areas for future research to better define the role of stress-immune pathways in mediating outcome following TBI.
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http://dx.doi.org/10.3389/fneur.2019.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491704PMC
April 2019

Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.

Authors:
Xiaoyu Liu Daniel P Nemeth Daniel B McKim Ling Zhu Damon J DiSabato Olimpia Berdysz Gowthami Gorantla Braedan Oliver Kristina G Witcher Yufen Wang Christina E Negray Rekha S Vegesna John F Sheridan Jonathan P Godbout Matthew J Robson Randy D Blakely Phillip G Popovich Staci D Bilbo Ning Quan

Immunity 2019 Mar;50(3):764-766

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http://dx.doi.org/10.1016/j.immuni.2019.02.012DOI Listing
March 2019

Reply to: Microglia, Monocytes, and the Recurrence of Anxiety in Stress-Sensitized Mice.

Authors:
Kristina G Witcher Wenyuan Yin John F Sheridan Jonathan P Godbout

Biol Psychiatry 2019 06 8;85(12):e69-e70. Epub 2019 Mar 8.

Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio; Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio; Division of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2019.01.026DOI Listing
June 2019

Repeated social defeat in female mice induces anxiety-like behavior associated with enhanced myelopoiesis and increased monocyte accumulation in the brain.

Authors:
Wenyuan Yin Natalie R Gallagher Caroline M Sawicki Daniel B McKim Jonathan P Godbout John F Sheridan

Brain Behav Immun 2019 05 23;78:131-142. Epub 2019 Jan 23.

Department of Neuroscience, The Ohio State University Wexner Medical Center, 333 W. 10th Ave., Columbus, OH 43210, United States; Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, 460 Medical Center Dr, Columbus, OH 43210, United States; Division of Biosciences, The Ohio State University College of Dentistry, 4157 Postle Hall, 305 W. 12th Ave., Columbus, OH 43210, United States. Electronic address:

Anxiety and mood disorders affect both men and women. The majority of experimental models of stress, however, are completed using only male animals. For repeated social defeat (RSD), a rodent model, this is due to the inherent difficulty in eliciting male aggression toward female mice. To address this limitation, a recent study showed that a DREADD-based activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) was effective in inducing aggressive behavior in male mice towards females in a social defeat paradigm. Therefore, the goal of this study was to determine if this modified version of RSD in females elicited behavioral, physiological, and immune responses similar to those reported in males. Here, we show that female mice subjected to RSD with the male DREADD aggressor developed anxiety-like behavior and social avoidance. These behavioral alterations coincided with enhanced neuronal and microglial activation in threat-appraisal regions of the brain. Moreover, stressed female mice had an enhanced peripheral immune response characterized by increased myelopoiesis, release of myeloid cells into circulation, and monocyte accumulation in the spleen and brain. These results are consistent with previously reported findings that male mice exposed to RSD exhibited increased fear and threat appraisal responses, enhanced myelopoiesis, myeloid cell release and trafficking, and anxiety-like behavior. These findings validate that RSD is a relevant model to study stress responses in female mice.
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http://dx.doi.org/10.1016/j.bbi.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488440PMC
May 2019

Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities.

Authors:
Xiaoyu Liu Daniel P Nemeth Daniel B McKim Ling Zhu Damon J DiSabato Olimpia Berdysz Gowthami Gorantla Braedan Oliver Kristina G Witcher Yufen Wang Christina E Negray Rekha S Vegesna John F Sheridan Jonathan P Godbout Matthew J Robson Randy D Blakely Phillip G Popovich Staci D Bilbo Ning Quan

Immunity 2019 02 22;50(2):317-333.e6. Epub 2019 Jan 22.

Institute for Behavioral Medicine Research, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain's IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.
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http://dx.doi.org/10.1016/j.immuni.2018.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759085PMC
February 2019

Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress.

Authors:
Caroline M Sawicki January K Kim Michael D Weber Timothy D Faw Daniel B McKim Kathryn M Madalena Jessica K Lerch D Michele Basso Michelle L Humeidan Jonathan P Godbout John F Sheridan

J Neurosci 2019 02 17;39(7):1139-1149. Epub 2018 Dec 17.

Division of Biosciences, Ohio State University College of Dentistry, Columbus, Ohio 43210,

Clinical studies indicate that psychosocial stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. Here we show that mechanical allodynia in male mice was increased with exposure to RSD. This stress-induced behavior corresponded with increased mRNA expression of several inflammatory genes, including IL-1β, TNF-α, CCL2, and TLR4 in the lumbar spinal cord. While there were several adhesion and chemokine-related genes increased in the lumbar spinal cord after RSD, there was no accumulation of monocytes or neutrophils. Notably, there was evidence of microglial activation selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar cord. Elimination of microglia using the colony stimulating factor 1 receptor antagonist PLX5622 from the brain and spinal cord prevented the development of mechanical allodynia in RSD-exposed mice. Microglial elimination also attenuated RSD-induced IL-1β, CCR2, and TLR4 mRNA expression in the lumbar spinal cord. Together, RSD-induced allodynia was associated with microglia-mediated inflammation within the dorsal horn of the lumbar spinal cord. Mounting evidence indicates that psychological stress contributes to the onset and progression of adverse nociceptive conditions. We show here that repeated social defeat stress causes increased pain sensitivity due to inflammatory signaling within the nociceptive circuits of the spinal cord. Studies here mechanistically tested the role of microglia in the development of pain by stress. Pharmacological ablation of microglia prevented stress-induced pain sensitivity. These findings demonstrate that microglia are critical mediators in the induction of pain conditions by stress. Moreover, these studies provide a proof of principle that microglia can be targeted as a therapeutic strategy to mitigate adverse pain conditions.
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http://dx.doi.org/10.1523/JNEUROSCI.2785-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381245PMC
February 2019

The Influence of Microglial Elimination and Repopulation on Stress Sensitization Induced by Repeated Social Defeat.

Authors:
Michael D Weber Daniel B McKim Anzela Niraula Kristina G Witcher Wenyuan Yin Carly G Sobol Yufen Wang Caroline M Sawicki John F Sheridan Jonathan P Godbout

Biol Psychiatry 2019 04 25;85(8):667-678. Epub 2018 Oct 25.

Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio; Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Background: Stress is associated with an increased prevalence of anxiety and depression. Repeated social defeat (RSD) stress in mice increases the release of monocytes from the bone marrow that are recruited to the brain by microglia. These monocytes enhance inflammatory signaling and augment anxiety. Moreover, RSD promotes stress sensitization, in which exposure to acute stress 24 days after cessation of RSD causes anxiety recurrence. The purpose of this study was to determine whether microglia were critical to stress sensitization and exhibited increased reactivity to subsequent acute stress or immune challenge.

Methods: Mice were exposed to RSD, microglia were eliminated by colony-stimulating factor 1 receptor antagonism (PLX5622) and allowed to repopulate, and responses to acute stress or immune challenge (lipopolysaccharide) were determined 24 days after RSD sensitization.

Results: Microglia maintained a unique messenger RNA signature 24 days after RSD. Moreover, elimination of RSD-sensitized microglia prevented monocyte accumulation in the brain and blocked anxiety recurrence following acute stress (24 days). When microglia were eliminated prior to RSD and repopulated and mice were subjected to acute stress, there was monocyte accumulation in the brain and anxiety in RSD-sensitized mice. These responses were unaffected by microglial elimination/repopulation. This may be related to neuronal sensitization that persisted 24 days after RSD. Following immune challenge, there was robust microglial reactivity in RSD-sensitized mice associated with prolonged sickness behavior. Here, microglial elimination/repopulation prevented the amplified immune reactivity ex vivo and in vivo in RSD-sensitized mice.

Conclusions: Microglia and neurons remain sensitized weeks after RSD, and only the immune reactivity component of RSD-sensitized microglia was prevented by elimination/repopulation.
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http://dx.doi.org/10.1016/j.biopsych.2018.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440809PMC
April 2019

Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis.

Authors:
Daniel B McKim Wenyuan Yin Yufen Wang Steve W Cole Jonathan P Godbout John F Sheridan

Cell Rep 2018 11;25(9):2552-2562.e3

Division of Biosciences, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA. Electronic address:

Psychosocial stress accelerates myelopoietic production of monocytes and neutrophils that contributes to a variety of health complications ranging from atherosclerosis to anxiety. Here, we show that social stress in mice mobilizes hematopoietic stem progenitor cells (HSPCs) from the bone marrow that enter circulation, engraft into the spleen, and establish a persistent extramedullary hematopoietic depot. These splenic progenitors actively proliferate and differentiate into multiple cell types, including monocytes, neutrophils, and erythrocytes. Splenic erythropoiesis partially abrogates stress-induced anemia. Repeated injection with isoprenaline induces progenitor mobilization to the spleen, identifying a key role for β-adrenergic signaling. Moreover, protracted splenic production of CD11b cells persists for at least 24 days after the cessation of social stress. Thus, chronic stress establishes a persistent extramedullary hematopoietic depot that can modify a wide range of chronic disease processes and alter homeostasis of the bi-directional regulatory axis between the nervous and immune systems.
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http://dx.doi.org/10.1016/j.celrep.2018.10.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342493PMC
November 2018

Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge.

Authors:
Shane M O'Neil Kristina G Witcher Daniel B McKim Jonathan P Godbout

Acta Neuropathol Commun 2018 11 26;6(1):129. Epub 2018 Nov 26.

Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Microglia are the resident innate immune cells of the central nervous system. Limited turnover throughout the lifespan leaves microglia susceptible to age-associated dysfunction. Indeed, we and others have reported microglia develop a pro-inflammatory or "primed" profile with age, characterized by increased expression of inflammatory mediators (e.g., MHC-II, CD68, IL-1β). Moreover, immune challenge with lipopolysaccharide (LPS) causes an exaggerated and prolonged neuroinflammatory response mediated by primed microglia in the aged brain. Recent studies show colony-stimulating factor 1 receptor (CSF1R) antagonism results in rapid depletion of microglia without significant complications. Therefore, we hypothesized that CSF1R antagonist-mediated depletion of microglia in the aged brain would result in repopulation with new and unprimed microglia. Here we provide novel evidence that microglia in the brain of adult (6-8 weeks old) and aged (16-18 months old) BALB/c mice were depleted following 3-week oral PLX5622 administration. When CSF1R antagonism was stopped, microglia repopulated equally in the adult and aged brain. Microglial depletion and repopulation reversed age-associated increases in microglial CD68 lysosome enlargement and lipofuscin accumulation. Microglia-specific RNA sequencing revealed 511 differentially expressed genes with age. Of these, 117 genes were reversed by microglial repopulation (e.g., Apoe, Tgfb2, Socs3). Nevertheless, LPS challenge still induced an exaggerated microglial inflammatory response in the aged brain compared to adults. RNA sequencing of whole-brain tissue revealed an age-induced inflammatory signature, including reactive astrocytes, that was not restored by microglial depletion and repopulation. Furthermore, the microenvironment of the aged brain produced soluble factors that influenced developing microglia ex vivo and induced a profile primed to LPS challenge. Thus, the aged brain microenvironment promotes microglial priming despite repopulation of new microglia. Collectively, aged microglia proliferate and repopulate the brain, but these new cells still adopt a pro-inflammatory profile in the aged brain.
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http://dx.doi.org/10.1186/s40478-018-0636-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260864PMC
November 2018

Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety.

Authors:
Anzela Niraula Kristina G Witcher John F Sheridan Jonathan P Godbout

Biol Psychiatry 2019 04 10;85(8):679-689. Epub 2018 Oct 10.

Division of Biosciences, The Ohio State University, Columbus, Ohio; Department of Neuroscience, The Ohio State University, Columbus, Ohio; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio. Electronic address:

Background: Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress.

Methods: Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later.

Results: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell-sorted blood monocytes (CD11b/Ly6C) and brain monocytes (CD11b/CD45) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1β, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL-6.

Conclusions: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.
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http://dx.doi.org/10.1016/j.biopsych.2018.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440848PMC
April 2019

Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation.

Authors:
Kristina G Witcher Chelsea E Bray Julia E Dziabis Daniel B McKim Brooke N Benner Rachel K Rowe Olga N Kokiko-Cochran Phillip G Popovich Jonathan Lifshitz Daniel S Eiferman Jonathan P Godbout

Glia 2018 12 30;66(12):2719-2736. Epub 2018 Oct 30.

Department of Neuroscience, The Ohio State University, Columbus, Ohio.

Microglia undergo dynamic structural and transcriptional changes during the immune response to traumatic brain injury (TBI). For example, TBI causes microglia to form rod-shaped trains in the cerebral cortex, but their contribution to inflammation and pathophysiology is unclear. The purpose of this study was to determine the origin and alignment of rod microglia and to determine the role of microglia in propagating persistent cortical inflammation. Here, diffuse TBI in mice was modeled by midline fluid percussion injury (FPI). Bone marrow chimerism and BrdU pulse-chase experiments revealed that rod microglia derived from resident microglia with limited proliferation. Novel data also show that TBI-induced rod microglia were proximal to axotomized neurons, spatially overlapped with dense astrogliosis, and aligned with apical pyramidal dendrites. Furthermore, rod microglia formed adjacent to hypertrophied microglia, which clustered among layer V pyramidal neurons. To better understand the contribution of microglia to cortical inflammation and injury, microglia were eliminated prior to TBI by CSF1R antagonism (PLX5622). Microglial elimination did not affect cortical neuron axotomy induced by TBI, but attenuated rod microglial formation and astrogliosis. Analysis of 262 immune genes revealed that TBI caused profound cortical inflammation acutely (8 hr) that progressed in nature and complexity by 7 dpi. For instance, gene expression related to complement, phagocytosis, toll-like receptor signaling, and interferon response were increased 7 dpi. Critically, these acute and chronic inflammatory responses were prevented by microglial elimination. Taken together, TBI-induced neuronal injury causes microglia to structurally associate with neurons, augment astrogliosis, and propagate diverse and persistent inflammatory/immune signaling pathways.
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http://dx.doi.org/10.1002/glia.23523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542609PMC
December 2018

Bone Marrow-Derived Monocytes Drive the Inflammatory Microenvironment in Local and Remote Regions after Thoracic Spinal Cord Injury.

Authors:
Diana M Norden Timothy D Faw Daniel B McKim Rochelle J Deibert Lesley C Fisher John F Sheridan Jonathan P Godbout D Michele Basso

J Neurotrauma 2019 03 6;36(6):937-949. Epub 2018 Oct 6.

1 School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, Ohio.

Spinal cord injury (SCI) produces a toxic inflammatory microenvironment that negatively affects plasticity and recovery. Recently, we showed glial activation and peripheral myeloid cell infiltration extending beyond the epicenter through the remote lumbar cord after thoracic SCI. The presence and role of infiltrating monocytes is important, especially in the lumbar cord where locomotor central pattern generators are housed. Therefore, we compared the inflammatory profile of resident microglia and peripheral myeloid cells after SCI. Bone marrow chimeras received midthoracic contusive SCI, and trafficking was determined 1-7 days later. Fluorescence-activated cell (FAC) sorting showed similar infiltration timing of both neutrophils and macrophages in epicenter and lumbar regions. While neutrophil numbers were attenuated by day 3, macrophages remained unchanged at day 7, suggesting that macrophages have important long-term influence on the microenvironment. Nanostring gene array identified a strong proinflammatory profile of infiltrating macrophages relative to microglia at both epicenter and lumbar sites. Macrophages had elevated expression of inflammatory cytokines (IL-1β, IFNγ), chemokines (CCL2, CXCL2), mediators (COX-1, MMP-9), and receptors (CCR2, Ly6C), and decreased expression of growth promoting genes (GDNF, BDNF). Importantly, lumbar macrophages had elevated expression of active trafficking genes (CCR2, l-selectin, MMP-9) compared with epicenter macrophages. Further, acute rehabilitation exacerbated the inflammatory profile of infiltrated macrophages in the lumbar cord. Such high inflammatory potential and negative response to rehabilitation of infiltrating macrophages within lumbar locomotor central pattern generators likely impedes activity-dependent recovery. Therefore, limiting active trafficking of macrophages into the lumbar cord identifies a novel target for SCI therapies to improve locomotion.
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http://dx.doi.org/10.1089/neu.2018.5806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484351PMC
March 2019

Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2.

Authors:
Sabrina Francesca Lisboa Anzela Niraula Leonardo Barbosa Resstel Francisco Silveira Guimaraes Jonathan P Godbout John F Sheridan

Neuropsychopharmacology 2018 08 17;43(9):1924-1933. Epub 2018 Apr 17.

Division of Biosciences, Ohio State University, Columbus, OH, 43210, USA.

Psychosocial stress contributes to the development of psychiatric disorders. Repeated social defeat (RSD) is a murine stressor that causes a release of inflammatory monocytes into circulation. Moreover, RSD-induced anxiety-like behavior is dependent on the recruitment of these monocytes to the brain. Activation of the endocannabinoid (ECB) system may modulate both neuroendocrine and inflammatory responses mediated by stress. Therefore, we hypothesized that a cannabinoid receptor agonist would attenuate RSD-induced inflammation, anxiety, and stress sensitization. To test this hypothesis, mice received an injection of the synthetic cannabinoid receptor agonist, WIN55,212-2 (WIN; 1 mg/kg, intraperitoneally) daily for six consecutive days, 30 min before each exposure to RSD. Anxiety-like behavior, immune activation, neuroinflammation, and microglial reactivity were determined 14 h after RSD. RSD-induced anxiety-like behavior in the open field and in the EPM was reversed by WIN55,212-2. Moreover, WIN55,212-2 reduced the accumulation of inflammatory monocytes in circulation and brain after RSD and attenuated RSD-induced interleukin-1β (IL-1β) messenger RNA (mRNA) expression in microglia/macrophages. Increased ex vivo reactivity of microglia/monocytes to lipopolysaccharides (LPS) after RSD was also attenuated by WIN55,212-2. Next, fear expression, extinction, and recall were evaluated 24 and 48 h, respectively, after contextual fear conditioning, which took place 7 days after RSD. Here, RSD caused prolonged fear expression and impaired fear extinction recall, which was associated with increased IL-1β mRNA in the brain. Moreover, these stress-induced effects were reversed by WIN55,212-2. In conclusion, activation of cannabinoid receptors limited the immune and neuroinflammatory responses to RSD and reversed the short-term and long-term behavioral deficits associated with RSD.
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http://dx.doi.org/10.1038/s41386-018-0064-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046035PMC
August 2018

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer's Disease.

Authors:
Olga N Kokiko-Cochran Jonathan P Godbout

Front Immunol 2018 9;9:672. Epub 2018 Apr 9.

Department of Neuroscience, Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI). Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges. For example, recent evidence shows that the presence of beta-amyloid and phosphorylated tau protein, two hallmark features of AD that increase during normal aging, substantially alter the macrophage response to TBI. Additional data demonstrate that post-injury microglia are "primed" and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery. These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology. Therefore, the purpose of this review is to summarize experimental studies examining the relationship between TBI and development of AD-like pathology with an emphasis on the acute and chronic microglial and macrophage response following injury. Furthermore, studies will be highlighted that examine the degree to which beta-amyloid and tau accumulation as well as pre- and post-injury immune stressors influence outcome after TBI. Collectively, the studies described in this review suggest that the brain's immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.
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http://dx.doi.org/10.3389/fimmu.2018.00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900037PMC
June 2019

Corticosterone Production during Repeated Social Defeat Causes Monocyte Mobilization from the Bone Marrow, Glucocorticoid Resistance, and Neurovascular Adhesion Molecule Expression.

Authors:
Anzela Niraula Yufen Wang Jonathan P Godbout John F Sheridan

J Neurosci 2018 02 30;38(9):2328-2340. Epub 2018 Jan 30.

Division of Biosciences,

Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression. Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.
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http://dx.doi.org/10.1523/JNEUROSCI.2568-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830519PMC
February 2018

Effects of dermal wounding on distal primary tumor immunobiology in mice.

Authors:
Leah M Pyter Daniel B McKim Yasmin Husain Humberto Calero Jonathan P Godbout John F Sheridan Phillip T Marucha Christopher G Engeland

J Surg Res 2018 01 17;221:328-335. Epub 2017 Oct 17.

Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois.

Background: Before primary oral tumors are treated, various prophylactic procedures that require tissue repair are often necessary (e.g. biopsies, tooth extractions, radiation, and tracheotomies). Wound healing and tumor growth harness similar immune/inflammatory mechanisms. Our previous work indicates that tumors impair wound healing, although the extent to which tissue repair conversely influences tumor growth is poorly understood. Here, we test the hypothesis that dermal wound healing exacerbates primary tumor growth and influences tumor immunobiology.

Materials And Methods: Female, immunocompetent mice were inoculated subcutaneously with murine oral cancer cells (AT-84) to induce flank tumors. Half of the mice received dermal excisional wounds (4 × 3.5 mm diameter) on their dorsum 16 days later, whereas the skin of controls remained intact. Tumor and blood tissues were harvested 1 and 5 days post wounding, and tumor myeloid cell populations and inflammatory gene expression were measured. Circulating myeloid cells, cytokines, and corticosterone were also quantified.

Results: Wounding increased tumor mass, early tumor infiltration of macrophages, and tumor inflammatory gene expression. While wounding attenuated tumor growth-induced increases in circulating myeloid cells, no effects of wounding on circulating cytokine/endocrine measures were observed.

Conclusions: These results indicate that modest skin immune/inflammatory processes can enhance distal tumor growth and alter innate tumor immunity. The implication for this work is that, in the presence of a tumor, the benefits of tissue-damaging procedures that occur clinically must be weighed against the potential consequences for tumor biology.
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http://dx.doi.org/10.1016/j.jss.2017.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788460PMC
January 2018

Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated social defeat stress.

Authors:
Caroline M Sawicki January K Kim Michael D Weber Brant L Jarrett Jonathan P Godbout John F Sheridan Michelle Humeidan

Brain Behav Immun 2018 03 8;69:113-123. Epub 2017 Nov 8.

Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, USA; Department of Anesthesiology, The Ohio State University Wexner Medical Center, USA. Electronic address:

Objective: Mounting evidence indicates that stress influences the experience of pain. Exposure to psychosocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates the immune and behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like behavior.

Methods: Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, social avoidance behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following behavioral assessments.

Results: RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop social avoidance behavior. Neither drug affected stress-induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1β mRNA levels in the brain and spinal cord after RSD.

Conclusions: In this study, psychosocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or social avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or behavioral responses.
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http://dx.doi.org/10.1016/j.bbi.2017.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857417PMC
March 2018

MIF Inhibitor ISO-1 Protects Photoreceptors and Reduces Gliosis in Experimental Retinal Detachment.

Authors:
Bongsu Kim Rania Kusibati Tyler Heisler-Taylor Dimosthenis Mantopoulos Jiaxi Ding Mohamed H Abdel-Rahman Abhay R Satoskar Jonathan P Godbout Sanjoy K Bhattacharya Colleen M Cebulla

Sci Rep 2017 10 30;7(1):14336. Epub 2017 Oct 30.

Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, OH, 43212, USA.

Photoreceptor death and retinal gliosis underlie the majority of vision threatening retinal diseases including retinal detachment (RD). Although the underlying pathobiology of vision limiting processes in RD is not fully understood, inflammation is known to play a critical role. We conducted an iTRAQ proteomic screen of up- and down-regulated proteins in a murine model of RD to identify potential targetable candidates. Macrophage migration inhibitory factor (MIF) was identified and evaluated for neurotoxic and pro-gliotic effects during RD. Systemic administration of the MIF inhibitor ISO-1 significantly blocked photoreceptor apoptosis, outer nuclear layer (ONL) thinning, and retinal gliosis. ISO-1 and MIF knockout (MIFKO) had greater accumulation of Müller glia pERK expression in the detached retina, suggesting that Müller survival pathways might underlie the neuroprotective response. Our data show the feasibility of the MIF-inhibitor ISO-1 to block pathological damage responses in retinal detachment and provide a rationale to explore MIF inhibition as a potential therapeutic option for RD.
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http://dx.doi.org/10.1038/s41598-017-14298-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662618PMC
October 2017

Can Sustained Glia-Mediated Brain Inflammation After Repeated Concussive Brain Injury Be Detected In Vivo?

Authors:
Kristina G Witcher Jonathan P Godbout

JAMA Neurol 2017 01;74(1):23-25

Department of Neuroscience, Center for Brain and Spinal Cord Repair, Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus.

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http://dx.doi.org/10.1001/jamaneurol.2016.4539DOI Listing
January 2017

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection-Implications for Oncolytic Viral Therapy.

Authors:
Chelsea Bolyard W Hans Meisen Yeshavanth Banasavadi-Siddegowda Jayson Hardcastle Ji Young Yoo Eric S Wohleb Jeffrey Wojton Jun-Ge Yu Samuel Dubin Maninder Khosla Bo Xu Jonathan Smith Christopher Alvarez-Breckenridge Pete Pow-Anpongkul Flavia Pichiorri Jianying Zhang Matthew Old Dan Zhu Erwin G Van Meir Jonathan P Godbout Michael A Caligiuri Jianhua Yu Balveen Kaur

Clin Cancer Res 2017 Apr 9;23(7):1809-1819. Epub 2016 Nov 9.

Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio.

Brain angiogenesis inhibitor (BAI1) facilitates phagocytosis and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here, we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and Ingenuity Pathway Analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα-blocking antibodies and macrophages derived from mice were used. RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared with rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Furthermore, we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild-type/RAMBO virus in or wild-type non-tumor-bearing mice revealed the safety of this approach. We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380537PMC
April 2017

Neuroinflammation: the devil is in the details.

Authors:
Damon J DiSabato Ning Quan Jonathan P Godbout

J Neurochem 2016 10 4;139 Suppl 2:136-153. Epub 2016 May 4.

Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.

There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as 'neuroinflammatory'. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes. In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults. This article is part of the 60th anniversary supplemental issue.
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http://dx.doi.org/10.1111/jnc.13607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025335PMC
October 2016