Publications by authors named "Abdolmohamad Rostami"

129 Publications

CRISPR-mediated rapid generation of neural cell-specific knockout mice facilitates research in neurophysiology and pathology.

Mol Ther Methods Clin Dev 2021 Mar 18;20:755-764. Epub 2021 Feb 18.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Inducible conditional knockout mice are important tools for studying gene function and disease therapy, but their generation is costly and time-consuming. We introduced clustered regularly interspaced short palindromic repeats (CRISPR) and into an LSL-Cas9 transgene-carrying mouse line by using adeno-associated virus (AAV)-PHP.eB to rapidly knockout gene(s) specifically in central nervous system (CNS) cells of adult mice. in neurons and in astrocytes were knocked out 2 weeks after an intravenous injection of vector, with an efficiency comparable to that of inducible Cre- conditional knockout. For functional testing, we generated astrocyte-specific knockout mice, which exhibited a phenotype similar to mice with Cre--mediated knockout, in an animal model of multiple sclerosis (MS), an autoimmune disorder of the CNS. With this novel technique, neural cell-specific knockout can be induced rapidly (few weeks) and cost-effectively. Our study provides a new approach to building inducible conditional knockout mice, which would greatly facilitate research on CNS biology and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.omtm.2021.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940702PMC
March 2021

Role of extracellular vesicles in neurodegenerative diseases.

Prog Neurobiol 2021 Jun 19;201:102022. Epub 2021 Feb 19.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, 710119, China. Electronic address:

Extracellular vesicles (EVs) are heterogeneous cell-derived membranous structures that arise from the endosome system or directly detach from the plasma membrane. In recent years, many advances have been made in the understanding of the clinical definition and pathogenesis of neurodegenerative diseases, but translation into effective treatments is hampered by several factors. Current research indicates that EVs are involved in the pathology of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Besides, EVs are also involved in the process of myelin formation, and can also cross the blood-brain barrier to reach the sites of CNS injury. It is suggested that EVs have great potential as a novel therapy for the treatment of neurodegenerative diseases. Here, we reviewed the advances in understanding the role of EVs in neurodegenerative diseases and addressed the critical function of EVs in the CNS. We have also outlined the physiological mechanisms of EVs in myelin regeneration and highlighted the therapeutic potential of EVs in neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pneurobio.2021.102022DOI Listing
June 2021

Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model.

Immunology 2021 Jun 28;163(2):185-200. Epub 2021 Feb 28.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China.

Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4 T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114201PMC
June 2021

Interferon-γ/Interleukin-27 Axis Induces Programmed Death Ligand 1 Expression in Monocyte-Derived Dendritic Cells and Restores Immune Tolerance in Central Nervous System Autoimmunity.

Front Immunol 2020 26;11:576752. Epub 2020 Oct 26.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States.

Antigen (Ag)-specific tolerance induction by intravenous (i. v.) injection of high-dose auto-Ags has been explored for therapy of autoimmune diseases, including multiple sclerosis (MS). It is thought that the advantage of such Ag-specific therapy over non-specific immunomodulatory treatments would be selective suppression of a pathogenic immune response without impairing systemic immunity, thus avoiding adverse effects of immunosuppression. Auto-Ag i.v. tolerance induction has been extensively studied in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and limited clinical trials demonstrated that it is safe and beneficial to a subset of MS patients. Nonetheless, the mechanisms of i.v. tolerance induction are incompletely understood, hampering the development of better approaches and their clinical application. Here, we describe a pathway whereby auto-Ag i.v. injected into mice with ongoing clinical EAE induces interferon-gamma (IFN-γ) secretion by auto-Ag-specific CD4 T cells, triggering interleukin (IL)-27 production by conventional dendritic cells type 1 (cDC1). IL-27 then, signal transducer and activator of transcription 3 activation, induces programmed death ligand 1 (PD-L1) expression by monocyte-derived dendritic cells (moDCs) in the central nervous system of mice with EAE. PD-L1 interaction with programmed cell death protein 1 on pathogenic CD4 T cells leads to their apoptosis/anergy, resulting in disease amelioration. These findings identify a key role of the IFN-γ/IL-27/PD-L1 axis, involving T cells/cDC1/moDCs in the induction of i.v. tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.576752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649367PMC
October 2020

Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice.

Sci Transl Med 2020 11;12(568)

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven effective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous tolerance induction by injecting a myelin Ag used for triggering EAE. However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients. To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)-derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags. Intravenous Ol-EV injection reduced disease pathophysiology in a myelin Ag-dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4 T cells. Furthermore, we showed that human Ols also released EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system (CNS) autoimmunity in a myelin Ag-specific manner, without the need to identify the target Ag.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aba0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886371PMC
November 2020

A distinct GM-CSF T helper cell subset requires T-bet to adopt a T1 phenotype and promote neuroinflammation.

Sci Immunol 2020 10;5(52)

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing T helper (T) cells has been associated with several autoimmune diseases, suggesting a potential role in the pathogenesis of autoimmunity. However, the identity of GM-CSF-producing T cells has not been closely examined. Using single-cell RNA sequencing and high-dimensional single-cell mass cytometry, we identified eight populations of antigen-experienced CD45RACD4 T cells in blood of healthy individuals including a population of GM-CSF-producing cells, known as TGM, that lacked expression of signature transcription factors and cytokines of established T lineages. Using GM-CSF-reporter/fate reporter mice, we show that TGM cells are present in the periphery and central nervous system in a mouse model of experimental autoimmune encephalomyelitis. In addition to GM-CSF, human and mouse TGM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. TGM cells maintained their phenotype through several cycles of activation but up-regulated expression of T-bet and interferon-γ (IFN-γ) upon exposure to IL-12 in vitro and in the central nervous system of mice with autoimmune neuroinflammation. Although T-bet was not required for the development of TGM cells, it was essential for their encephalitogenicity. These findings demonstrate that TGM cells constitute a distinct population of T cells with lineage characteristics that are poised to adopt a T1 phenotype and promote neuroinflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.aba9953DOI Listing
October 2020

P7C3 attenuates CNS autoimmunity by inhibiting Th17 cell differentiation.

Cell Mol Immunol 2021 Jun 9;18(6):1565-1567. Epub 2020 Jul 9.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-020-0497-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166969PMC
June 2021

Primaquine elicits Foxp3 regulatory T cells with a superior ability to limit CNS autoimmune inflammation.

J Autoimmun 2020 11 25;114:102505. Epub 2020 Jun 25.

Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address:

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory conditions where inflammatory CD4 T cells play a major role. Forkhead box P3 (Foxp3) regulatory T (Treg) cells suppress inflammation and an increase in their numbers and activity is beneficial for MS and EAE. However, studies have shown that Treg cells can transdifferentiate to pathogenic Th17 cells under inflammatory conditions. Drugs that stimulate Treg cell induction and their resistance to inflammatory stimuli are necessary to develop effective therapies to treat MS. Here, we show that primaquine (PQ), an anti-malarial drug, suppresses EAE through the stimulation of Foxp3 Treg cells. PQ-elicited Treg cells are refractory to inflammatory stimuli and suppress EAE. Additionally, PQ-elicited Foxp3 Treg cells were more efficient in suppressing the proliferation of responder cells compared to PBS-elicited Treg cells. Although PQ does not directly induce Foxp3 Treg cell differentiation from naïve T cells, it modulated dendritic cells (DCs) to induce Foxp3 Treg cells in an indoleamine 2,3 dioxygenase (IDO)-dependent manner. Together, our results show that PQ elicits Foxp3 Treg cells with a superior suppressive activity to reduce EAE. PQ has the potential as a safe and effective treatment for MS and other CNS autoimmune inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2020.102505DOI Listing
November 2020

Comprehensive Analysis of the Immune and Stromal Compartments of the CNS in EAE Mice Reveal Pathways by Which Chloroquine Suppresses Neuroinflammation.

Brain Sci 2020 Jun 5;10(6). Epub 2020 Jun 5.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are neuroinflammatory diseases of the central nervous system (CNS), where leukocytes and CNS resident cells play important roles in disease development and pathogenesis. The antimalarial drug chloroquine (CQ) has been shown to suppress EAE by modulating dendritic cells (DCs) and Th17 cells. However, the mechanism of action by which CQ modulates EAE is far from being elucidated. Here, we comprehensively analyzed the CNS of CQ and PBS-treated EAE mice to identify and characterize the cells that are affected by CQ. Our results show that leukocytes are largely modulated by CQ and have a reduction in the expression of inflammatory markers. Intriguingly, CQ vastly modulated the CNS resident cells astrocytes, oligodendrocytes (OLs) and microglia (MG), with the latter producing IL-10 and IL-12p70. Overall, our results show a panoramic view of the cellular components that are affect by CQ and provide further evidence that drug repurposing of CQ will be beneficial to MS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10060348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349328PMC
June 2020

Bone marrow dendritic cells deficient for CD40 and IL-23p19 are tolerogenic .

Iran J Basic Med Sci 2020 Mar;23(3):287-292

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Objectives: In addition to pro-inflammatory role, dendritic cells (DCs) can also be anti-inflammatory when they acquire tolerogenic phenotype. In this study we tested the role of CD40 and IL-23p19 in antigen presenting function of bone marrow-derived DCs (BMDCs) by comparing BMDCs derived from CD40 knockout (CD40KO-DCs) and IL-23p19 (IL-23p19KO-DCs) knockout mice with those from C57BL/6 mice (Cont-DCs). We have focused on CD40 and IL-23, as these molecules have well established pro-inflammatory roles in a number of autoimmune and inflammatory diseases.

Materials And Methods: The expression of maturation markers MHC II and co-stimulatory molecules CD40, CD80, and CD86 was analyzed by flow cytometry, while the expression of CD40 and IL-23p19 was measured by RT-PCR. The capacity of BMDCs to activate CD4+ T cells was evaluated by 3H-thymidine incorporation, and the capacity of BMDCs to uptake antigen was evaluated using fluorescent OVA and flow cytometry.

Results: The lack of CD40 or IL-23p19 had no effect on uptake of FITC-OVA by the DCs, confirming their immature phenotype. Moreover, CD40KO-DCs had significantly reduced capacity to stimulate proliferation of CD4+ T cells. CD4+ T cells activated by CD40KO-DCs and IL-23p19KO-DCs produced significantly less IFN-γ (-value ≤0.05), while CD4+ T cells stimulated by IL-23p19KO-DCs produced less GM-CSF and more IL-10 than Cont-DCs.

Conclusion: This study shows that CD40KO-DCs and IL-23p19KO-DCs have a marked tolerogenic potency . Future studies should determine if and to what extent DCs lacking CD40 or IL-23 have a potential to be useful in therapy of autoimmune inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22038/IJBMS.2020.36160.8615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229508PMC
March 2020

The Long Road of Immunotherapeutics against Multiple Sclerosis.

Brain Sci 2020 May 11;10(5). Epub 2020 May 11.

NewDrug, Patras Science Park, 26500 Patras, Greece.

This commentary highlights novel immunomodulation and vaccine-based research against multiple sclerosis (MS) and reveals the amazing story that triggered this cutting-edge MS research in Greece and worldwide. It further reveals the interest and solid support of some of the world's leading scientists, including sixteen Nobel Laureates who requested from European leadership to take action in supporting Greece and its universities in the biggest ever financial crisis the country has encountered in the last decades. This support endorsed vaccine-based research on MS, initiated in Greece and Australia, leading to a worldwide network aiming to treat or manage disease outcomes. Initiatives by bright and determined researchers can result in frontiers science. We shed light on a unique story behind great research on MS which is a step forward in our efforts to develop effective treatments for MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10050288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287601PMC
May 2020

Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor-producing Th1 cells in CNS neuroinflammation.

Neurol Neuroimmunol Neuroinflamm 2020 07 5;7(4). Epub 2020 May 5.

From the Department of Neurology (F.S., R.T., Z.L., G.-X.Z., A.R.), Thomas Jefferson University, Philadelphia, PA. Dr. Safavi is now at National Institute of Health, NINDS, Bethesda, MD.

Objective: To study the immunomodulatory effect of dimethyl fumarate (DF) on granulocyte macrophage colony-stimulating factor (GM-CSF) production in CD4 T cells in experimental autoimmune encephalomyelitis (EAE) and human peripheral blood mononuclear cells (PBMCs).

Methods: We collected splenocytes and CD4 T cells from C57BL/6 wild-type and interferon (IFN)-γ-deficient mice. For human PBMCs, venous blood was collected from healthy donors, and PBMCs were collected using the Percoll gradient method. Cells were cultured with anti-CD3/28 in the presence/absence of DF for 3 to 5 days. Cells were stained and analyzed by flow cytometry. Cytokines were measured by ELISA in cell supernatants. For in vivo experiments, EAE was induced by myelin oligodendrocyte glycoprotein and mice were treated with oral DF or vehicle daily.

Results: DF acts directly on CD4 T cells and suppresses GM-CSF-producing Th1 not Th17 or single GM-CSF T cells in EAE. In addition, GM-CSF suppression depends on the IFN-γ pathway. We also show that DF specifically suppresses Th1 and GM-CSF-producing Th1 cells in PBMCs from healthy donors.

Conclusions: We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4 T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217662PMC
July 2020

A dual effect of ursolic acid to the treatment of multiple sclerosis through both immunomodulation and direct remyelination.

Proc Natl Acad Sci U S A 2020 04 6;117(16):9082-9093. Epub 2020 Apr 6.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2000208117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183235PMC
April 2020

RNA-Binding Protein HuR Promotes Th17 Cell Differentiation and Can Be Targeted to Reduce Autoimmune Neuroinflammation.

J Immunol 2020 04 13;204(8):2076-2087. Epub 2020 Mar 13.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107;

Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help find a novel therapeutic target for treating Th17 cell-mediated diseases. In this study, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by posttranscriptionally regulating transcription factors and and receptor expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation in C57BL/6J mice. Knockout of HuR altered the transcriptome of Th17 cells characterized by reducing the levels of RORγt, IRF4, RUNX1, and T-bet, thereby reducing the number of pathogenic IL-17IFN-γCD4 T cells in the spleen during experimental autoimmune encephalomyelitis. In keeping with the fact that HuR increased the abundance of adhesion molecule VLA-4 on Th17 cells, knockout of HuR impaired splenic Th17 cell migration to the CNS and abolished the disease. Accordingly, targeting HuR by its inhibitor DHTS inhibited splenic Th17 cell differentiation and reduced experimental autoimmune encephalomyelitis severity. In sum, we uncovered the molecular mechanism of HuR regulating Th17 cell functions, underscoring the therapeutic value of HuR for treatment of autoimmune neuroinflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1900769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534900PMC
April 2020

Potential roles of extracellular vesicles in the pathophysiology, diagnosis, and treatment of autoimmune diseases.

Int J Biol Sci 2020 1;16(4):620-632. Epub 2020 Jan 1.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.

Since extracellular vesicles (EVs) were discovered in 1983 in sheep reticulocytes samples, they have gradually attracted scientific attention and become a topic of great interest in the life sciences field. EVs are small membrane particles, released by virtually every cell that carries a variety of functional molecules. Their main function is to deliver messages to the surrounding area in both physiological and pathological conditions. Initially, they were thought to be either cell debris, signs of cell death, or unspecific structures. However, accumulating evidence support a theory that EVs are a universal mechanism of communication. Thanks to their biological characteristics and functions, EVs are likely to represent a promising strategy for obtaining pathogen information, identifying therapeutic targets and selecting specific biomarkers for a variety of diseases, such as autoimmune diseases. In this review, we provide a brief overview of recent progress in the study of the biology and functions of EVs. We also discuss their roles in diagnosis and therapy, with particular emphasis on autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.39629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990925PMC
February 2021

Evaluation of the effect of GM-CSF blocking on the phenotype and function of human monocytes.

Sci Rep 2020 01 31;10(1):1567. Epub 2020 Jan 31.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine that prompts the proliferation of bone marrow-derived macrophages and granulocytes. In addition to its effects as a growth factor, GM-CSF plays an important role in chronic inflammatory autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Reports have identified monocytes as the primary target of GM-CSF; however, its effect on monocyte activation has been under-estimated. Here, using flow cytometry and ELISA we show that GM-CSF induces an inflammatory profile in human monocytes, which includes an upregulated expression of HLA-DR and CD86 molecules and increased production of TNF-α and IL-1β. Conversely, blockage of endogenous GM-CSF with antibody treatment not only inhibited the inflammatory profile of these cells, but also induced an immunomodulatory one, as shown by increased IL-10 production by monocytes. Further analysis with qPCR, flow cytometry and ELISA experiments revealed that GM-CSF blockage in monocytes stimulated production of the chemokine CXCL-11, which suppressed T cell proliferation. Blockade of CXCL-11 abrogated anti-GM-CSF treatment and induced inflammatory monocytes. Our findings show that anti-GM-CSF treatment induces modulatory monocytes that act in a CXCL-11-dependent manner, a mechanism that can be used in the development of novel approaches to treat chronic inflammatory autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-58131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994676PMC
January 2020

IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.

J Immunol 2020 02 18;204(3):531-539. Epub 2019 Dec 18.

Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R mice correlates with increased numbers of GM-CSF CD4 T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4 T cells through the modulation of DCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1801113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197375PMC
February 2020

Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update.

Front Immunol 2019 4;10:1265. Epub 2019 Jun 4.

Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Conversely, a protective role has also been described in other autoimmune diseases where humoral responses are detrimental such as myasthenia gravis (MG), Hashimoto's thyroiditis (HT), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In this review, we aimed for a comprehensive analysis of literature data on the multiple roles of GM-CSF in autoimmue diseases and possible therapeutic strategies that target GM-CSF production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.01265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593264PMC
October 2020

Generation of Oligodendrocyte Progenitor Cells From Mouse Bone Marrow Cells.

Front Cell Neurosci 2019 5;13:247. Epub 2019 Jun 5.

The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China.

Oligodendrocyte progenitor cells (OPCs) are a subtype of glial cells responsible for myelin regeneration. Oligodendrocytes (OLGs) originate from OPCs and are the myelinating cells in the central nervous system (CNS). OLGs play an important role in the context of lesions in which myelin loss occurs. Even though many protocols for isolating OPCs have been published, their cellular yield remains a limit for clinical application. The protocol proposed here is novel and has practical value; in fact, OPCs can be generated from a source of autologous cells without gene manipulation. Our method represents a rapid, and high-efficiency differentiation protocol for generating mouse OLGs from bone marrow-derived cells using growth-factor defined media. With this protocol, it is possible to obtain mature OLGs in 7-8 weeks. Within 2-3 weeks from bone marrow (BM) isolation, after neurospheres formed, the cells differentiate into Nestin Sox2 neural stem cells (NSCs), around 30 days. OPCs specific markers start to be expressed around day 38, followed by RIPO4 around day 42. CNPase mature OLGs are finally obtained around 7-8 weeks. Further, bone marrow-derived OPCs exhibited therapeutic effect in shiverer (Shi) mice, promoting myelin regeneration and reducing the tremor. Here, we propose a method by which OLGs can be generated starting from BM cells and have similar abilities to subventricular zone (SVZ)-derived cells. This protocol significantly decreases the timing and costs of the OLGs differentiation within 2 months of culture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2019.00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561316PMC
June 2019

The selective retinoic acid receptor-α agonist AM580 fails to control autoimmune neuroinflammation.

Cell Mol Immunol 2019 08 3;16(8):727-729. Epub 2019 Jun 3.

Department of Neurology, Thomas Jefferson University, 900 Walnut Street, Suite 300, Philadelphia, PA, 19107, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-019-0238-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804666PMC
August 2019

Combination Therapy With Fingolimod and Neural Stem Cells Promotes Functional Myelination Through a Non-immunomodulatory Mechanism.

Front Cell Neurosci 2019 5;13:14. Epub 2019 Feb 5.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States.

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an brain slice culture model, and in the developing CNS of healthy postnatal mice . Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2019.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371042PMC
February 2019

Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4 CD1273G11 Regulatory T Cell Subset.

Front Immunol 2018 13;9:2562. Epub 2018 Nov 13.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, United States.

Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4 T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4 CD1273G11 regulatory T cell subset and . By contrast, IL-27 treated immature DCs fail to modulate development of the CD4CD1273G11 regulatory T cell sub-population and . Our results suggest that IL-27 may break immune tolerance induced by LPS-stimulated mature DCs through modulating development of a specific CD4 regulatory T cell subset mediated by 3G11 and CD127. Our data reveal a new cellular regulatory mechanism of IL-27 that targets DC-mediated immune responses in autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244609PMC
October 2019

Chloroquine-treated dendritic cells require STAT1 signaling for their tolerogenic activity.

Eur J Immunol 2018 07 17;48(7):1228-1234. Epub 2018 Apr 17.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas, UNICAMP, Campinas, Brazil.

MS and EAE are T cell-driven autoimmune diseases of the CNS where IL-17-producing Th17 cells promote damage and are pathogenic. Conversely, tolerogenic DCs induce Treg cells and suppress Th17 cells. Chloroquine (CQ) suppresses EAE through the modulation of DCs by unknown mechanisms. Here, we show that STAT 1 is necessary for CQ-induced tolerogenic DCs (tolDCs) to efficiently suppress EAE. We observed that CQ induces phosphorylation of STAT1 in DCs in vivo and in vitro. Genetic blockage of STAT1 abrogated the suppressive activity of CQ-treated DCs. Opposed to its WT counterparts, CQ-treated STAT1 BMDCs were unable to suppress Th17 cells and increased EAE severity. Our findings show that STAT1 is a major signaling pathway in CQ-induced tolDCs and may shed light on new therapeutic avenues for the induction of tolDCs in autoimmune diseases such as MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201747362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473787PMC
July 2018

Elevated expression of granulocyte-macrophage colony-stimulating factor receptor in multiple sclerosis lesions.

J Neuroimmunol 2018 04 22;317:45-54. Epub 2017 Dec 22.

Department of Neurology, Division of Multiple Sclerosis and Neuroimmunology, Thomas Jefferson University, 900 Walnut Street, Suite 300, Philadelphia, PA 19107, USA. Electronic address:

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease that disproportionately affects young adults, leading to disability and high costs to society. Infiltration of T cells and monocytes into the central nervous system (CNS) is critical for disease initiation and progression. However, despite a great deal of effort the molecular mechanisms by which immune cells initiate and perpetuate CNS damage in MS have not yet been elucidated. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by pathogenic Th1 and Th17 cells is critical for the recruitment of monocytes into the CNS during the initial stage of disease. We and others have recently shown that, compared with healthy individuals, MS patients have greater numbers of CD4 and CD8 T cells that produce GM-CSF. Here, we describe the expression of GM-CSF and its receptor, GM-CSFR, in normal brain and MS lesions. Our data show that in acute and chronic MS lesions, microglia and astrocytes have upregulated expression of GM-CSFR; in addition, we show that GM-CSF-associated molecules are also upregulated in MS lesions. These findings further strengthen the argument that GM-CSF signaling contributes to MS pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2017.12.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935005PMC
April 2018

Interaction of RNA-binding protein HuR and miR-466i regulates GM-CSF expression.

Sci Rep 2017 12 8;7(1):17233. Epub 2017 Dec 8.

Department of Neurology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by T helper 17 (Th17) cells plays an essential role in autoimmune diseases. Transcriptional regulation of Th17 cell differentiation has been extensively studied, but post-transcriptional regulation of Th17 cell differentiation has remained less well characterized. The RNA-binding protein HuR functions to promote the stability of target mRNAs via binding the AU-rich elements of the 3' untranslated region (3'UTR) of numerous pro-inflammatory cytokines including IL-4, IL-13, IL-17 and TNF-α. However, whether HuR regulates GM-CSF expression in Th17 cells has not been fully investigated. Here we showed that HuR conditional knockout (KO) Th17 cells have decreased GM-CSF mRNA in comparison with wild-type (WT) Th17 cells, and that HuR binds directly to GM-CSF mRNA 3'UTR. Interestingly, HuR deficiency increased the levels of certain microRNA expression in Th17 cells; for example, miR-466i functioned to mediate GM-CSF and IL-17 mRNA decay, which was confirmed by in vitro luciferase assay. Furthermore, we found that HuR promoted Mxi1 expression to inhibit certain miRNA expression. Taken together, these findings indicate that interaction of HuR and miR-466i orchestrates GM-CSF expression in Th17 cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-17371-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722853PMC
December 2017

Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells.

Front Immunol 2017 27;8:1392. Epub 2017 Oct 27.

Department of Neurology, Jefferson Hospital for Neuroscience, Thomas Jefferson University, Philadelphia, PA, United States.

Peripheral tolerance to autoantigens is induced suppression of self-reactive lymphocytes, stimulation of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Interleukin (IL)-27 induces tolerogenic DCs and Treg cells; however, it is not known whether IL-27 is important for tolerance induction. We immunized wild-type (WT) and IL-27 receptor (WSX-1) knockout mice with MOG for induction of experimental autoimmune encephalomyelitis and intravenously (i.v.) injected them with MOG after onset of disease to induce i.v. tolerance. i.v. administration of MOG reduced disease severity in WT mice, but was ineffective in mice. IL-27 signaling in DCs was important for tolerance induction, whereas its signaling in T cells was not. Further mechanistic studies showed that IL-27-dependent tolerance relied on cooperation of distinct subsets of spleen DCs with the ability to induce T cell-derived IL-10 and IFN-γ. Overall, our data show that IL-27 is a key cytokine in antigen-induced peripheral tolerance and may provide basis for improvement of antigen-specific tolerance approaches in multiple sclerosis and other autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.01392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663690PMC
October 2017

DABIL-2 recombinant fusion toxin effect on lymphocyte- and macrophage-producing cytokine subpopulation cells in experimentally induced demyelinating disease in mice.

Immunopharmacol Immunotoxicol 2017 Dec 20;39(6):318-329. Epub 2017 Sep 20.

e Department of Neurology , Thomas Jefferson University , Philadelphia , PA , USA.

Context: We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4 cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.

Objectives: The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.

Materials And Methods: The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.

Results: C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DABIL-2 treatment reduced CD3CD4, CD3CD8, CD4CD8, CD3IL-2, CD3IFN-γ and CD3TNF-α T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19 B-cells positive for IL-2 or CD11b in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3CD8, CD4CD8, CD3CD25 populations on day 16, and lymph node CD3IL-10 and peripheral blood CD3CD25 populations on day 24.

Discussion And Conclusions: Our study demonstrates that DABIL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08923973.2017.1369099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705025PMC
December 2017