scholarly journals Differential roles of microglia and monocytes in the inflamed central nervous system

2014 ◽  
Vol 211 (8) ◽  
pp. 1533-1549 ◽  
Author(s):  
Ryo Yamasaki ◽  
Haiyan Lu ◽  
Oleg Butovsky ◽  
Nobuhiko Ohno ◽  
Anna M. Rietsch ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Expression Profiles ◽  
Disease Onset ◽  
Gene Expression Profiles ◽  
Autoimmune Encephalomyelitis ◽  
Block Face ◽  
Human Disorder ◽  
Autoimmune Demyelination ◽  
New Strategies ◽  
Experimental Autoimmune

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

Modulation of experimental autoimmune encephalomyelitis through colonisation of the gut with Escherichia coli

2020 ◽  
pp. 1-16 ◽  
Author(s):  
J.E. Libbey ◽  
J.M.S. Sanchez ◽  
B.A. Fleming ◽  
D.J. Doty ◽  
A.B. DePaula-Silva ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Disease Onset ◽  
Probiotic Bacterium ◽  
Coli Strain ◽  
Preclinical Model ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a neuro-inflammatory autoimmune disease of the central nervous system (CNS) that affects young adults. It is characterised by the development of demyelinating lesions and inflammation within the CNS. Although the causes of MS are still elusive, recent work using patient samples and experimental animal models has demonstrated a strong relationship between the gut microbiota and its contribution to CNS inflammation and MS. While there is no cure for MS, alteration of the gut microbiota composition through the use of probiotics is a very promising treatment. However, while most recent works have focused on the use of probiotics to modify pre-existing disease, little is known about its role in protecting from the establishment of MS. In this study, we determined whether colonisation with the probiotic bacterium Escherichia coli strain Nissle 1917 (EcN) could be used as a prophylactic strategy to prevent or alter the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We found that double gavage (two doses) of EcN before induction of EAE delayed disease onset and decreased disease severity. We also found that EcN-treated mice had decreased amounts of perivascular cuffing, CD4+ T cell infiltration into the CNS, together with significantly decreased absolute numbers of Th1 cells, and reduced activation of microglia. Although further studies are necessary to comprehend the exact protective mechanisms induced, our study supports a promising use of EcN as a probiotic for the prevention of MS.

scholarly journals Gene expression profiling of the Notch-AhR-IL22 axis at homeostasis and in response to tissue injury

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Marc Weidenbusch ◽  
Severin Rodler ◽  
Shangqing Song ◽  
Simone Romoli ◽  
Julian A. Marschner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Tissue Injury ◽  
Expression Profiles ◽  
Notch Pathway ◽  
Gene Expression Profiles ◽  
Sterile Inflammation ◽  
Specific Gene ◽  
Specific Gene Expression

Notch and interleukin-22 (IL-22) signaling are known to regulate tissue homeostasis and respond to injury in humans and mice, and the induction of endogenous aryl hydrocarbon receptor (Ahr) ligands through Notch links the two pathways in a hierarchical fashion. However in adults, the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TNF-α ADAM metalloprotease converting enzyme (TACE), PSEN1, basigin (BSG)/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL-22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in ten mature murine and human organs. Additionally, the expression of these genes was assessed in murine models of acute sterile inflammation and progressive fibrosis. We show that there are organ-specific gene expression profiles of the Notch-AhR-IL22 axis in humans and mice. Although there is an overall interspecies congruency, specific differences between human and murine expression signatures do exist. In murine tissues with AHR/ARNT expression CYP1A1 and IL-22 were correlated with HES5 and HEYL expression, while in human tissues no such correlation was found. Notch and AhR signaling are involved in renal inflammation and fibrosis with specific gene expression changes in each model. Despite the presence of all Notch pathway molecules in the kidney and a model-specific induction of Notch ligands, IL-22 was only up-regulated in acute inflammation, but rapidly down-regulated during regeneration. This implies that for targeting injury responses, e.g. via IL-22, species-specific differences, injury type and time points have to be considered.

scholarly journals The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease

2008 ◽  
Vol 205 (4) ◽  
pp. 811-823 ◽  
Author(s):  
Thaddeus Carlson ◽  
Mark Kroenke ◽  
Praveen Rao ◽  
Thomas E. Lane ◽  
Benjamin Segal
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Th17 Cells ◽  
Polymorphonuclear Leukocytes ◽  
Autoimmune Encephalomyelitis ◽  
Cxc Chemokine ◽  
The Central Nervous System ◽  
Autoimmune Demyelination ◽  
Clinical Deficits ◽  
Experimental Autoimmune

The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.

scholarly journals Modification of the Disease Progression in Mice with Experimental Autoimmune Encephalomyelitis Using Anti-Mitotic Compounds

2021 ◽  
Author(s):  
◽  
Kevin Patrick Crume
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Peloruside A ◽  
Proliferating Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>Multiple sclerosis (MS) is a multi-faceted disease, and is believed to be caused by an autoimmune response to myelin antigens in the central nervous system. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS. manifests itself in various forms that parallel many aspects of MS, including the appearance of symptoms, initiation events, and pathophysiology. The hallmark of any immune response is the antigen-specific proliferation of immune cells, and during the initiation events of EAE, proliferating CD4+ T cells are the primary mediators of disease. This thesis explores if targeting these proliferating cells with the anti-mitotic compounds paclitaxel and peloruside A can delay or prevent the unset of EAE, thus providing a novel therapeutic avenue for MS research. The anti-cancer compound, paclitaxel, is an anti-mitotic drug that prevents microtubule depolymerisation. Although paclitaxel has been used in the clinical setting to treat cancer for over a decade, it has been determined that paclitaxel stimulates murine toll-like receptor 4 (TLR4) complex, which is the major LPS receptor. A novel microtubule-stabilising compound, peloruside, is currently subject to intensive investigations due to its functional similarity to paclitaxel. The results from this project found that peloruside and paclitaxel inhibited the proliferation of mitogen-stimulated splenocytes with IC50 values of 83 nM and 30 nM, respectively, but did not affect the viability of non-proliferating cells In contrast to paclitaxel, peloruside did not cause the TLR4-mediated production of the inflammatory mediators. TNF-epsilon, IL-12, and nitric oxide, when cultured with IFN-epsilon stimulated murine macrophages. Interestingly, when LPS was included with either paclitaxel or peloruside A, both drugs decreased the production of TNF-e and nitric oxide from macrophages, suggesting that microtubule-stabilising compounds may have anti-inflammatory effects. To identify any immunomodifying effects of paclitaxel in vivo, paclitaxel was administered to mice that were immunised with the myelin protein MOG in complete Freund's adjuvant (CFA) to induce EAE. When Taxol was administered to mice for 5 consecutive days immediately following CFA/MOG immunisation, the onset of EAE was delayed by approximately I week. Moreover, the administration of peloruside following the same treatment regime also resulted in a similar delay of disease onset. Taxol treatments, however, lead to significant mortality in immunised, but not unimmunised mice. Interestingly, although Taxol is an anti-mitotic drug, the proliferation of antigen-specific T cells was not inhibited in vivo by the Taxol treatment. The findings revealed in this thesis present an opportunity to pursue a new avenue of research for the therapeutic treatment of MS sufferers, and possibly other inflammatory autoimmune disorders.</p>

scholarly journals Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis

Brain ◽  
2020 ◽  
Author(s):  
Hardeep Kataria ◽  
Christopher G Hart ◽  
Arsalan Alizadeh ◽  
Michael Cossoy ◽  
Deepak K Kaushik ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Spinal Cord Lesions ◽  
Neuregulin 1 ◽  
Chondroitin Sulphate Proteoglycans ◽  
New Findings ◽  
Experimental Autoimmune

Abstract Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1β1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1β1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1β1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1β1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1β1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1β1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1β1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1β1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1β1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

scholarly journals Damage to the Optic Chiasm in Myelin Oligodendrocyte Glycoprotein–Experimental Autoimmune Encephalomyelitis Mice

2014 ◽  
Vol 7 ◽  
pp. MRI.S19750 ◽  
Author(s):  
Sheryl L. Herrera ◽  
Vanessa L. Palmer ◽  
Heather Whittaker ◽  
Blair Cardigan Smith ◽  
Annie Kim ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Optic Chiasm ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Mr Images ◽  
Autoimmune Encephalomyelitis ◽  
Apparent Diffusion ◽  
Hematoxylin And Eosin ◽  
Magnetic Resonance Imaging Mri ◽  
Experimental Autoimmune

Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)–experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin–stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis.

Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1755-1761 ◽  
Author(s):  
Emanuela Zappia ◽  
Simona Casazza ◽  
Enrico Pedemonte ◽  
Federica Benvenuto ◽  
Ivan Bonanni ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Lymphoid Organs ◽  
Autoimmune Encephalomyelitis ◽  
Autoimmune Attack ◽  
Experimental Autoimmune

Abstract We studied the immunoregulatory features of murine mesenchymal stem cells (MSCs) in vitro and in vivo. MSCs inhibited T-cell receptor (TCR)-dependent and -independent proliferation but did not induce apoptosis on T cells. Such inhibition was paired with a decreased interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and was partially reversed by interleukin-2 (IL-2). Thus, we used MSCs to treat myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. We injected intravenously 1 × 106 MSCs before disease onset (preventive protocol) and at different time points after disease occurrence (therapeutic protocol). MSC administration before disease onset strikingly ameliorated EAE. The therapeutic scheme was effective when MSCs were administered at disease onset and at the peak of disease but not after disease stabilization. Central nervous system (CNS) pathology showed decreased inflammatory infiltrates and demyelination in mice that received transplants of MSCs. T-cell response to MOG and mitogens from MSC-treated mice was inhibited and restored by IL-2 administration. Upon MSC transfection with the enhanced green fluorescent protein (eGFP), eGFP+ cells were detected in the lymphoid organs of treated mice. These data suggest that the immunoregulatory properties of MSCs effectively interfere with the autoimmune attack in the course of EAE inducing an in vivo state of T-cell unresponsiveness occurring within secondary lymphoid organs. (Blood. 2005; 106:1755-1761)

scholarly journals Experimental Autoimmune Encephalomyelitis Induction in Genetically B Cell–deficient Mice

1996 ◽  
Vol 184 (6) ◽  
pp. 2271-2278 ◽  
Author(s):  
Susan D. Wolf ◽  
Bonnie N. Dittel ◽  
Fridrika Hardardottir ◽  
Charles A. Janeway
Keyword(s):  
T Cells ◽  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Immune Modulation ◽  
Disease Onset ◽  
Central Nervous System Disease ◽  
Autoimmune Encephalomyelitis ◽  
Deficient Mice ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model for autoimmune central nervous system disease mediated by CD4 T cells. To examine the role of B cells in the induction of EAE, we used B10.PL (I-Au) mice rendered deficient in B cells by deletion of their μ chain transmembrane region (B10.PLμMT). By immunizing B10.PL and B10.PLμMT mice with the NH-terminal myelin basic protein encephalitogenic peptide Ac1-11, we observed no difference in the onset or severity of disease in the absence of mature B cells. There was, however, a greater variation in disease onset, severity, and especially of recovery in the B cell–deficient mice compared to controls. B10.PLμMT mice rarely returned to normal in the absence of B cells. Taken together, our data suggest that B cells do not play a role in the activation of encephalitogenic T cells, but may contribute to the immune modulation of acute EAE. The mechanisms to explain these effects are discussed.

scholarly journals S100B Protein as a Therapeutic Target in Multiple Sclerosis: The S100B Inhibitor Arundic Acid Protects from Chronic Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 22 (24) ◽  
pp. 13558
Author(s):  
Chiara Camponeschi ◽  
Maria De Carluccio ◽  
Susanna Amadio ◽  
Maria Elisabetta Clementi ◽  
Beatrice Sampaolese ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Treated Group ◽  
S100b Protein ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune Encephalomyelitis Mouse ◽  
Clinical Scores ◽  
Experimental Autoimmune

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment.

scholarly journals A systematic survey of lipids across mouse tissues

2014 ◽  
Vol 306 (8) ◽  
pp. E854-E868 ◽  
Author(s):  
Mohit Jain ◽  
Soeun Ngoy ◽  
Sunil A. Sheth ◽  
Raymond A. Swanson ◽  
Eugene P. Rhee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mass Spectrometry ◽  
Tissue Injury ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Specific ◽  
Integrative Physiology ◽  
Lipid Species ◽  
Mouse Tissues ◽  
And Function

Lipids are a diverse collection of macromolecules essential for normal physiology, but the tissue distribution and function for many individual lipid species remain unclear. Here, we report a mass spectrometry survey of lipid abundance across 18 mouse tissues, detecting ∼1,000 mass spectrometry features, of which we identify 179 lipids from the glycerolipids, glycerophospholipids, lysophospholipids, acylcarnitines, sphingolipids, and cholesteryl ester classes. Our data reveal tissue-specific organization of lipids and can be used to generate testable hypotheses. For example, our data indicate that circulating triglycerides positively and negatively associated with future diabetes in humans are enriched in mouse adipose tissue and liver, respectively, raising hypotheses regarding the tissue origins of these diabetes-associated lipids. We also integrate our tissue lipid data with gene expression profiles to predict a number of substrates of lipid-metabolizing enzymes, highlighting choline phosphotransferases and sterol O-acyltransferases. Finally, we identify several tissue-specific lipids not present in plasma under normal conditions that may be of interest as biomarkers of tissue injury, and we show that two of these lipids are released into blood following ischemic brain injury in mice. This resource complements existing compendia of tissue gene expression and may be useful for integrative physiology and lipid biology.

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