Publications by authors named "James C Cronk"

8 Publications

  • Page 1 of 1

Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia.

J Exp Med 2018 06 11;215(6):1627-1647. Epub 2018 Apr 11.

Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA

Peripherally derived macrophages infiltrate the brain after bone marrow transplantation and during central nervous system (CNS) inflammation. It was initially suggested that these engrafting cells were newly derived microglia and that irradiation was essential for engraftment to occur. However, it remains unclear whether brain-engrafting macrophages (beMφs) acquire a unique phenotype in the brain, whether long-term engraftment may occur without irradiation, and whether brain function is affected by the engrafted cells. In this study, we demonstrate that chronic, partial microglia depletion is sufficient for beMφs to populate the niche and that the presence of beMφs does not alter behavior. Furthermore, beMφs maintain a unique functional and transcriptional identity as compared with microglia. Overall, this study establishes beMφs as a unique CNS cell type and demonstrates that therapeutic engraftment of beMφs may be possible with irradiation-free conditioning regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20180247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987928PMC
June 2018

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.

JCI Insight 2017 01 26;2(2):e88257. Epub 2017 Jan 26.

Center for Brain Immunology and Glia.

Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in -null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.88257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256138PMC
January 2017

Unexpected cellular players in Rett syndrome pathology.

Neurobiol Dis 2016 08 14;92(Pt A):64-71. Epub 2015 May 14.

Center for Brain Immunology and Glia, Department of Neuroscience, Graduate Program in Neuroscience and Medical Scientist Training Program, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease was identified over a decade ago, a significant gap still remains in both our clinical and scientific understanding of its pathogenesis. Neurons are known to be primary players in pathology, with their dysfunction being the key in Rett syndrome. While studies in mice have demonstrated a clear causative - and potential therapeutic - role for neurons in Rett syndrome, recent work has suggested that other tissues also contribute significantly to progression of the disease. Indeed, Rett syndrome is known to present with several common peripheral pathologies, such as osteopenia, scoliosis, gastrointestinal problems including nutritional defects, and general growth deficit. Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets. A new picture is emerging in which neurons both initiate and drive pathology, while dysfunction of other cell types and peripheral tissues exacerbate disease, possibly amplifying further neurologic problems, and ultimately result in a positive feedback loop of progressively worsening symptoms. Here, we review what is known about neuronal and non-neuronal cell types, and discuss how this new, integrative understanding of the disease may allow for additional clinical and scientific pathways for treating and understanding Rett syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2015.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644494PMC
August 2016

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Immunity 2015 Apr;42(4):679-91

Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2015.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407145PMC
April 2015

Microglia - the brain's busy bees.

F1000Prime Rep 2013 Dec 3;5:53. Epub 2013 Dec 3.

Center for Brain Immunology and Glia, Department of Neuroscience and Graduate Program in Neuroscience, Medical Scientist Training Program, School of Medicine, University of Virginia Charlottesville, VA 22908 USA.

Recent years have seen significant changes in the way scientists view microglia and their role in health and disease. For decades, it was presumed that microglia were stationary, inactive immune cells in the brain, waiting for an immunologic insult to call them into action. In contrast, modern imaging techniques have revealed that microglia are constantly in motion, surveying their environment. Lineage tracing studies have led to the understanding that microglia are part of a larger family of cells, called tissue-resident macrophages, which arise from early yolk sac progenitors during embryogenesis and engraft nearly every organ in the body. Microglia, and all tissue-resident macrophages, rely on signaling through CD115 (the colony stimulating factor 1 receptor) for survival, primarily through the ligand, macrophage colony-stimulating factor. However, it is now understood that some microglia have a specific need for another CD115 ligand, Interleukin-34, which is only shared with Langerhans cells in the skin. In contrast to classical views, recent evidence suggests that the primary functions of microglia may occur during postnatal neurodevelopment and adult homeostasis, as absence or impairment of microglia results in a pathology separate from inflammatory immune function. In summary, these advances suggest that microglia might eventually be utilized or targeted to improve disease outcomes via encouraging or enhancing their health-promoting homeostatic functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12703/P5-53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854698PMC
December 2013

The role of microglia in brain maintenance: implications for Rett syndrome.

Trends Immunol 2013 Mar 31;34(3):144-50. Epub 2012 Oct 31.

Center for Brain Immunology and Glia and Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.

The role of microglia in central nervous system (CNS) pathology has been studied extensively, and more recently, examination of microglia in the healthy brain has yielded important insights into their many functions. It was long assumed that microglia were essentially quiescent cells, unless provoked into activation, which was considered a hallmark of disease. More recently, however, it has become increasingly clear that they are extraordinarily dynamic cells, constantly sampling their environment and adjusting to exquisitely delicate stimuli. Along these lines, our laboratory has identified a new and unexpected role for microglial phagocytosis - or lack thereof - in the pathophysiology of Rett syndrome, a neurodevelopmental disease caused by mutation of the gene encoding methyl-CpG binding protein (MECP)2. We have shown that specific expression of wild type Mecp2 in myeloid cells of Mecp2-null mice is sufficient to arrest major symptoms associated with this devastating disease. This beneficial effect, however, is abolished if phagocytic activity of microglia is inhibited. Here, we discuss microglial origins, the role of microglia in brain development and maintenance, and the phenomenon of microglial augmentation by myeloid progenitor cells in the adult brain. Finally, we address in some detail the beneficial roles of microglia as clinical targets in Rett syndrome and other neurological disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.it.2012.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566274PMC
March 2013

IL-4 in the brain: a cytokine to remember.

J Immunol 2012 Nov;189(9):4213-9

Department of Neuroscience and Graduate Program in Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA 22908, USA.

IL-4 has been extensively studied in the context of its role in immunity. Accumulating evidence indicates, however, that it also plays a critical role in higher functions of the normal brain, such as memory and learning. In this review, we summarize current knowledge of the basic immunology of IL-4, describe how and where this cytokine appears to operate in normal brain function, and propose a hypothesis concerning its potential role in neurological pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1202246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481177PMC
November 2012

Wild-type microglia arrest pathology in a mouse model of Rett syndrome.

Nature 2012 Mar 18;484(7392):105-9. Epub 2012 Mar 18.

Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.

Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature10907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321067PMC
March 2012