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1.
Glia ; 71(4): 991-1001, 2023 04.
Article in English | MEDLINE | ID: mdl-36511515

ABSTRACT

Multiple sclerosis (MS) is a focal inflammatory and demyelinating disease. The inflammatory infiltrates consist of macrophages/microglia, T and B cells. Remyelination (RM) is an endogenous repair process which frequently fails in MS patients. In earlier studies, T cells either promoted or impaired RM. Here, we used the combined cuprizone/MOG-EAE model to further dissect the functional role of T cells for RM. The combination of MOG immunization with cuprizone feeding targeted T cells to the corpus callosum and increased the extent of axonal injury. Global gene expression analyses demonstrated significant changes in the inflammatory environment; however, additional MOG immunization did not alter the course of RM. Our results suggest that the inflammatory environment in the combined model affects axons and oligodendrocytes differently and that oligodendroglial lineage cells might be less susceptible to T cell mediated injury.


Subject(s)
Demyelinating Diseases , Multiple Sclerosis , Remyelination , Animals , Mice , Axons , Corpus Callosum/metabolism , Cuprizone/toxicity , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Disease Models, Animal , Mice, Inbred C57BL , Multiple Sclerosis/metabolism , Myelin Sheath/physiology , Oligodendroglia/metabolism , Remyelination/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
2.
Brain ; 144(4): 1152-1166, 2021 05 07.
Article in English | MEDLINE | ID: mdl-33899089

ABSTRACT

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n = 15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut-CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.


Subject(s)
Dietary Supplements , Enteritis/pathology , Linoleic Acids, Conjugated/pharmacology , Monocytes/immunology , Multiple Sclerosis, Relapsing-Remitting/pathology , Adult , Animals , Autoimmunity/drug effects , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Enteritis/immunology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Multiple Sclerosis, Relapsing-Remitting/immunology , Pilot Projects , Proof of Concept Study
3.
Proc Natl Acad Sci U S A ; 115(34): E8017-E8026, 2018 08 21.
Article in English | MEDLINE | ID: mdl-30072431

ABSTRACT

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.


Subject(s)
Autoimmunity , Lymphocyte Activation , Mitochondria , Nuclear Receptor Subfamily 4, Group A, Member 1 , Oxygen Consumption/immunology , T-Lymphocytes , Animals , Central Nervous System/immunology , Central Nervous System/metabolism , Gene Expression Profiling , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Mice , Mice, Knockout , Mitochondria/genetics , Mitochondria/immunology , Mitochondria/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Nuclear Receptor Subfamily 4, Group A, Member 1/immunology , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Receptors, Estrogen/genetics , Receptors, Estrogen/immunology , Receptors, Estrogen/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , ERRalpha Estrogen-Related Receptor
4.
PLoS One ; 12(9): e0184985, 2017.
Article in English | MEDLINE | ID: mdl-28926619

ABSTRACT

The nuclear receptor Liver X Receptor (LXR) is a ligand-activated transcription factor that has been implicated in control of chronic inflammation by downregulating pro-inflammatory T cell responses. An impaired function of regulatory T cells, a subset of CD4+ T cells with a crucial role in maintaining lymphocytes homeostasis and immune regulation, is frequently observed in chronic inflammatory diseases. We observed that pharmacological activation of LXR in T cells not only resulted in a thorough suppression of Th1 and Th17 polarization in vitro, but also significantly induced regulatory T cells (Treg) cell differentiation in a receptor-specific fashion. In line with this, systemic LXR activation by oral treatment of mice with the LXR agonist GW3965 induced gut-associated regulatory T cells in vivo. Importantly, such LXR-activated Tregs had a higher suppressive capacity in functional in vitro coculture assays with effector T cells. Our data thus point towards a dual role of LXR-mediated control of inflammation by suppression of pro-inflammatory T cells and reciprocal induction of regulatory T cells.


Subject(s)
Liver X Receptors/metabolism , T-Lymphocytes, Regulatory/metabolism , Administration, Oral , Animals , Benzoates/pharmacology , Benzylamines/pharmacology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/drug effects , Coculture Techniques , Cytokines/analysis , Enzyme-Linked Immunosorbent Assay , Intestinal Mucosa/metabolism , Intestines/immunology , Liver X Receptors/agonists , Liver X Receptors/genetics , Lymph Nodes/drug effects , Lymph Nodes/immunology , Mice , Mice, Knockout , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/drug effects , Th1 Cells/cytology , Th1 Cells/drug effects , Th1 Cells/immunology , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/immunology , Transforming Growth Factor beta/pharmacology
5.
J Neuroinflammation ; 14(1): 66, 2017 03 28.
Article in English | MEDLINE | ID: mdl-28351411

ABSTRACT

BACKGROUND: The nuclear receptor farnesoid-X-receptor (FXR; NR1H4) is expressed not only in the liver, gut, kidney and adipose tissue but also in the immune cells. FXR has been shown to confer protection in several animal models of inflammation, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). FXR agonists are currently tested in clinical trials for treatment of human metabolic diseases. The beneficial effect of FXR agonists in EAE suggests that FXR might represent a potential target in inflammatory-demyelinating CNS diseases, such as MS. In MS, oligodendrocytes not only undergo cell death but also contribute to remyelination. This repair mechanism is impaired due to a differentiation block of oligodendroglial progenitor cells. Activation of other nuclear receptors that heterodimerize with FXR promote oligodendroglial differentiation. Therefore, we wanted to address the functional relevance of FXR for glial cells, especially for oligodendroglial differentiation. METHODS: We isolated primary murine oligodendrocytes from FXR-deficient (FXR Ko) and wild-type (WT) mice and determined the effect of FXR deficiency and activation on oligodendroglial differentiation by analysing markers of oligodendroglial progenitor cells (OPCs) and mature oligodendrocytes (OLs) using qRT-PCR and immunocytochemistry. Additionally, we determined whether FXR activation modulates the pro-inflammatory profile of astrocytes or microglia and whether this may subsequently modulate oligodendroglial differentiation. These in vitro studies were complemented by histological analyses of oligodendrocytes in FXR Ko mice. RESULTS: FXR is expressed by OPCs and mature oligodendrocytes. However, lack of FXR did not affect oligodendroglial differentiation in vitro or in vivo. Furthermore, activation of FXR using the synthetic agonist GW4064 did not affect oligodendroglial differentiation, remyelination in an ex vivo model or the expression of pro-inflammatory molecules in astrocytes or microglia. Concordantly, no effects of supernatants from macrophages cultured in the presence of GW4064 were observed regarding a possible indirect impact on oligodendroglial differentiation. CONCLUSIONS: Our data suggest that FXR is dispensable for oligodendroglial differentiation and that FXR agonists, such as GW4064, represent a potential therapeutic approach for MS which specifically targets peripheral immune cells including macrophages but not brain-resident cells, such as oligodendrocytes, astrocytes or microglia.


Subject(s)
Oligodendroglia/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cells, Cultured , Cerebellum/cytology , Cytokines/genetics , Cytokines/metabolism , Dose-Response Relationship, Drug , In Vitro Techniques , Isoxazoles/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Basic Protein/genetics , Myelin Basic Protein/metabolism , Nerve Tissue Proteins/metabolism , Nitric Oxide/metabolism , Nogo Proteins/metabolism , Oligodendrocyte Transcription Factor 2 , Oligodendroglia/drug effects , RNA, Messenger/metabolism , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
6.
Stroke ; 48(4): 1061-1069, 2017 04.
Article in English | MEDLINE | ID: mdl-28292872

ABSTRACT

BACKGROUND AND PURPOSE: Peripheral immune cell infiltration contributes to neural injury after ischemic stroke. However, in contrast to lymphocytes and neutrophils, the role of different monocyte/macrophage subsets remains to be clarified. Therefore, we evaluated the effects of selective and unselective monocyte/macrophage depletion and proinflammatory (M1-) and anti-inflammatory (M2-) macrophage transfer on the outcome after experimental cerebral ischemia. METHODS: To assess short-term effects of monocytes/macrophages in acute ischemic stroke, mice underwent transient middle cerebral artery occlusion and received either clodronate liposomes for unselective macrophage depletion, MC-21-antibody for selective depletion of proinflammatory Ly-6Chigh monocytes, or proinflammatory (M1-) or anti-inflammatory (M2-) macrophage transfer. In addition, the impact of MC-21-antibody administration and M2-macrophage transfer on long-term neural recovery was investigated after photothrombotic stroke. Neurobehavioral tests were used to analyze functional outcomes, infarct volumes were determined, and immunohistochemical analyses were performed to characterize the postischemic inflammatory reaction. RESULTS: Selective and unselective monocyte/macrophage depletion and M1- and M2-macrophage transfer did not influence tissue damage and neurobehavioral outcomes in the acute phase after middle cerebral artery occlusion. Beyond, selective depletion of Ly-6Chigh monocytes and M2-macrophage transfer did not have an impact on neural recovery after photothrombotic stroke. CONCLUSIONS: Targeting different monocyte/macrophage subsets has no impact on outcome after ischemic stroke in mice. Altogether, our study could not identify monocytes/macrophages as relevant therapeutic targets in acute ischemic stroke.


Subject(s)
Brain Ischemia/immunology , Inflammation/immunology , Macrophages/immunology , Monocytes/immunology , Stroke/immunology , Animals , Brain Ischemia/etiology , Disease Models, Animal , Infarction, Middle Cerebral Artery/complications , Mice , Random Allocation , Stroke/etiology
7.
Proc Natl Acad Sci U S A ; 113(41): E6182-E6191, 2016 10 11.
Article in English | MEDLINE | ID: mdl-27671636

ABSTRACT

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4+ T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immune-regulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.


Subject(s)
Autoimmunity/genetics , B7-H1 Antigen/genetics , Brain/immunology , Brain/metabolism , Endothelial Cells/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Animals , B7-H1 Antigen/metabolism , Blood-Brain Barrier/metabolism , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental , Gene Knockout Techniques , Genetic Predisposition to Disease , Mice , Mice, Transgenic , Mortality , Permeability , Severity of Illness Index , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
8.
Acta Neuropathol ; 132(3): 413-31, 2016 09.
Article in English | MEDLINE | ID: mdl-27383204

ABSTRACT

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.


Subject(s)
Autoimmunity/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-10/immunology , Myeloid Cells/metabolism , Receptors, Cytoplasmic and Nuclear/immunology , T-Lymphocytes/cytology , Animals , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/metabolism , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred C57BL , T-Lymphocytes/metabolism
9.
J Autoimmun ; 67: 90-101, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26584738

ABSTRACT

The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen-independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro-inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity.


Subject(s)
Autoimmunity , Macrophage Activation/immunology , Macrophages/immunology , Macrophages/metabolism , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Sodium Chloride, Dietary/administration & dosage , Animals , Autoimmunity/drug effects , Biomarkers , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental , Humans , Immunophenotyping , MAP Kinase Signaling System , Macrophage Activation/drug effects , Macrophages/drug effects , Mice , Monocytes/immunology , Monocytes/metabolism , Phenotype
10.
Mult Scler ; 22(2): 133-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26447064

ABSTRACT

In recent years it has become increasingly clear that, alongside genetic risk factors, environmental factors strongly influence the incidence and severity of multiple sclerosis (MS). Based on observations from epidemiological studies, the potential contribution of dietary habits has lately been a matter of debate. Recently it was shown that high salt conditions promote pathogenic T-cell responses and aggravate autoimmunity in an animal model of MS, suggesting that high dietary salt intake might promote central nervous system (CNS) autoimmunity. However, so far, not much is known about the influence of dietary salt intake on MS disease pathology. Here, we discuss the association of dietary salt levels and MS with a special focus on the mechanisms of salt-mediated modulation of the different cell types critically involved in the pathophysiology of MS.


Subject(s)
Autoimmunity/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Endothelial Cells/immunology , Macrophages/immunology , Microbiota/immunology , Multiple Sclerosis/immunology , Sodium Chloride, Dietary/immunology , T-Lymphocytes/immunology , Animals , Diet/statistics & numerical data , Disease Models, Animal , Epithelial Cells/immunology , Humans , Multiple Sclerosis/epidemiology , Myeloid Cells/immunology , Risk Factors
11.
J Immunol ; 195(8): 3584-95, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26378076

ABSTRACT

It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4(+) T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated TH17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.


Subject(s)
B7-H1 Antigen/immunology , Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Multiple Sclerosis/immunology , Programmed Cell Death 1 Receptor/immunology , Th17 Cells/immunology , Animals , B7-H1 Antigen/genetics , Cell Differentiation/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Mice , Mice, Knockout , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Programmed Cell Death 1 Receptor/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Th17 Cells/pathology
12.
Acta Neuropathol ; 130(2): 247-61, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25943886

ABSTRACT

Multiple sclerosis is the most frequent demyelinating disease in the CNS that is characterized by inflammatory demyelinating lesions and axonal loss, the morphological correlate of permanent clinical disability. Remyelination does occur, but is limited especially in chronic disease stages. Despite effective immunomodulatory therapies that reduce the number of relapses the progressive disease phase cannot be prevented. Therefore, promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy. A number of pathways have been identified that may contribute to impaired remyelination in MS lesions, among them the Wnt/ß-catenin pathway. Here, we demonstrate that indometacin, a non-steroidal anti-inflammatory drug (NSAID) that has been also shown to modulate the Wnt/ß-catenin pathway in colorectal cancer cells promotes differentiation of primary human and murine oligodendrocytes, myelination of cerebellar slice cultures and remyelination in cuprizone-induced demyelination. Our in vitro experiments using GSK3ß inhibitors, luciferase reporter assays and oligodendrocytes expressing a mutant, dominant stable ß-catenin indicate that the mechanism of action of indometacin depends on GSK3ß activity and ß-catenin phosphorylation. Indometacin might represent a promising treatment option to enhance endogenous remyelination in MS patients.


Subject(s)
Indomethacin/pharmacology , Myelin Sheath/drug effects , Neuroprotective Agents/pharmacology , Oligodendroglia/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Differentiation/drug effects , Cell Line, Tumor , Cells, Cultured , Cerebellum/drug effects , Cerebellum/pathology , Cerebellum/physiology , Cuprizone , Demyelinating Diseases/drug therapy , Demyelinating Diseases/pathology , Demyelinating Diseases/physiopathology , Disease Models, Animal , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Male , Mice, Inbred C57BL , Mice, Transgenic , Myelin Sheath/physiology , Neural Stem Cells/drug effects , Neural Stem Cells/pathology , Neural Stem Cells/physiology , Oligodendroglia/pathology , Oligodendroglia/physiology , Tissue Culture Techniques , Wnt Signaling Pathway/drug effects
13.
Ann Clin Transl Neurol ; 2(2): 119-30, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25750917

ABSTRACT

OBJECTIVE: To evaluate the influence of Fingolimod treatment on B-cell subset composition and function in multiple sclerosis patients and its potential clinical relevance. METHODS: Subset composition and cytokine production of B cells derived from peripheral blood mononuclear cells from multiple sclerosis patients under Fingolimod treatment, untreated multiple sclerosis patients and healthy controls were analyzed by flow cytometry and ELISA. Migration of lymphocyte subsets across primary human brain microvascular endothelial cells was assessed in an in vitro transmigration assay. Cell numbers and composition of B-cell subsets in cerebrospinal fluid and peripheral blood were determined by flow cytometry. Regulatory B-cell frequencies were correlated with parameters of disease stability. RESULTS: Within the peripheral B-cell compartment of Fingolimod-treated patients, the proportion of regulatory B cells (CD38(+)CD27(-)CD24(+)CD5(+)) was significantly increased as compared to treatment-naïve multiple sclerosis patients and to healthy controls, and significantly more regulatory B cells produced Interleukin-10. Fingolimod treatment enhanced the capacity of regulatory B cells to transmigrate across brain endothelial cells in an in vitro model of the blood-brain-barrier. In line with these findings, the cerebrospinal fluid/blood ratio of total B cells and regulatory B cells was strongly increased by Fingolimod treatment, and patients exhibited increased regulatory B-cell frequencies in the cerebrospinal fluid. Finally, elevated regulatory B-cell percentages in the periphery significantly correlated with clinical and paraclinical disease stability. INTERPRETATION: These data suggest a novel and as yet unrecognized role of Fingolimod in correction of the imbalance between regulatory and effector B-cell functions in multiple sclerosis both by direct effects and indirect partitioning effects on B-cell subpopulations.

14.
PLoS One ; 8(9): e73439, 2013.
Article in English | MEDLINE | ID: mdl-24066047

ABSTRACT

Besides their role in immune system host defense, there is growing evidence that macrophages may also be important regulators of salt homeostasis and blood pressure by a TonEBP-VEGF-C dependent buffering mechanism. As macrophages are known to accumulate in the skin of rats fed under high salt diet conditions and are pivotal for removal of high salt storage, the question arose how macrophages sense sites of high sodium storage. Interestingly, we observed that macrophage-like RAW264.7 cells, murine bone marrow-derived macrophages and peritoneal macrophages recognize NaCl hypertonicity as a chemotactic stimulus and migrate in the direction of excess salt concentration by using an in vitro transwell migration assay. While RAW264.7 cells migrated toward NaCl in a dose-dependent fashion, no migratory response toward isotonic or hypotonic media controls, or other osmo-active agents, e.g. urea or mannitol, could be detected. Interestingly, we could not establish a specific role of the osmoprotective transcription factor TonEBP in regulating salt-dependent chemotaxis, since the specific migration of bone marrow-derived macrophages following RNAi of TonEBP toward NaCl was not altered. Although the underlying mechanism remains unidentified, these data point to a thus far unappreciated role for NaCl-dependent chemotaxis of macrophages in the clearance of excess salt, and suggest the existence of novel NaCl sensor/effector circuits, which are independent of the TonEBP system.


Subject(s)
Chemotaxis/drug effects , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/drug effects , Animals , Cell Line , Cell Movement/drug effects , Cell Movement/genetics , Macrophages, Peritoneal/metabolism , Mice , RNA Interference , Sodium Chloride/pharmacology , Transcription Factors/genetics , Transcription Factors/metabolism
15.
Glia ; 61(10): 1712-23, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23922240

ABSTRACT

The mechanisms involved in oligodendroglial cell death in human demyelinating diseases are only partly understood. Here, we demonstrate that the BH3 only protein Puma, but not Noxa, is essential for oligodendroglial cell death in toxic demyelination induced by the copper chelator cuprizone. Primary oligodendrocytes derived from Noxa- or Puma-deficient mice showed comparable differentiation to wild-type cells, but Puma-deficient oligodendrocytes were less susceptible to spontaneous, staurosporine, or nitric oxide-induced cell death. Furthermore, Puma was expressed in oligodendrocytes in multiple sclerosis (MS) lesions and Puma mRNA levels were upregulated in primary human oligodendrocytes upon cell death induction by staurosporine. Our data demonstrate that Puma is pivotal for oligodendroglial cell death induced by different cell death stimuli and might play a role in oligodendroglial cell death in MS.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Oligodendroglia/physiology , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Proteins/metabolism , Adult , Aged , Analysis of Variance , Animals , Animals, Newborn , Apoptosis Regulatory Proteins/deficiency , Brain/cytology , Cell Death/drug effects , Cell Death/genetics , Cells, Cultured , Cuprizone/toxicity , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Demyelinating Diseases/prevention & control , Disease Models, Animal , Female , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , In Situ Nick-End Labeling , Interferon-gamma/pharmacology , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Multiple Sclerosis/pathology , Oligodendroglia/drug effects , Peptide Fragments/pharmacology , Proto-Oncogene Proteins c-bcl-2/deficiency , Tumor Suppressor Proteins/deficiency
16.
Brain ; 135(Pt 5): 1586-605, 2012 May.
Article in English | MEDLINE | ID: mdl-22447120

ABSTRACT

During central nervous system autoimmunity, interactions between infiltrating immune cells and brain-resident cells are critical for disease progression and ultimately organ damage. Here, we demonstrate that local cross-talk between invading autoreactive T cells and auto-antigen-presenting myeloid cells within the central nervous system results in myeloid cell activation, which is crucial for disease progression during experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. This T cell-mediated licensing of central nervous system myeloid cells triggered astrocytic CCL2-release and promoted recruitment of inflammatory CCR2(+)-monocytes, which are the main effectors of disease progression. By employing a cell-specific knockout model, we identify the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in myeloid cells as key regulator of their disease-determining interactions with autoreactive T cells and brain-resident cells, respectively. LysM-PPARγ(KO) mice exhibited disease exacerbation during the effector phase of experimental autoimmune encephalomyelitis characterized by enhanced activation of central nervous system myeloid cells accompanied by pronounced local CCL2 production and inflammatory monocyte invasion, which finally resulted in increased demyelination and neuronal damage. Pharmacological PPARγ activation decreased antigen-specific T cell-mediated licensing of central nervous system myeloid cells, reduced myeloid cell-mediated neurotoxicity and hence dampened central nervous system autoimmunity. Importantly, human monocytes derived from patients with multiple sclerosis clearly responded to PPARγ-mediated control of proinflammatory activation and production of neurotoxic mediators. Furthermore, PPARγ in human monocytes restricted their capacity to activate human astrocytes leading to dampened astrocytic CCL2 production. Together, interference with the disease-promoting cross-talk between central nervous system myeloid cells, autoreactive T cells and brain-resident cells represents a novel therapeutic approach that limits disease progression and lesion development during ongoing central nervous system autoimmunity.


Subject(s)
Autoimmunity/physiology , Central Nervous System/immunology , Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/pathology , Myeloid Cells/physiology , PPAR gamma/metabolism , Analysis of Variance , Animals , Animals, Newborn , Antigens, CD/metabolism , Autoimmunity/immunology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Cerebellum/cytology , Coculture Techniques , Cytokines/metabolism , Disease Models, Animal , Embryo, Mammalian , Encephalomyelitis, Autoimmune, Experimental/immunology , Flow Cytometry , Freund's Adjuvant/adverse effects , Gene Knockdown Techniques , Glycoproteins/administration & dosage , Green Fluorescent Proteins/genetics , Hippocampus/cytology , Humans , Hypoglycemic Agents/administration & dosage , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Knockout , Monocytes/physiology , Myelin-Oligodendrocyte Glycoprotein , Myeloid Cells/immunology , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , PPAR gamma/deficiency , Peptide Fragments/administration & dosage , Pioglitazone , RNA, Small Interfering/metabolism , Receptors, CCR2/metabolism , T-Lymphocytes , Thiazolidinediones/administration & dosage
17.
J Exp Med ; 206(10): 2079-89, 2009 Sep 28.
Article in English | MEDLINE | ID: mdl-19737866

ABSTRACT

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-beta/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). We identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a key negative regulator of human and mouse Th17 differentiation. PPAR gamma activation in CD4(+) T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR gamma involved inhibition of TGF-beta/IL-6-induced expression of ROR gamma t in T cells. Pharmacologic activation of PPAR gamma prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR gamma t promoter in T cells, thus interfering with ROR gamma t transcription. Both T cell-specific PPAR gamma knockout and endogenous ligand activation revealed the physiological role of PPAR gamma for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4(+) T cells from healthy controls and MS patients were strongly susceptible to PPAR gamma-mediated suppression of Th17 differentiation. In summary, we report a PPAR gamma-mediated T cell-intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR gamma represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/prevention & control , Multiple Sclerosis/prevention & control , PPAR gamma/physiology , T-Lymphocytes, Helper-Inducer/cytology , Animals , Cell Differentiation , DNA-Binding Proteins/metabolism , Humans , Interleukin-17/physiology , Mice , Mice, Inbred C57BL , Nuclear Receptor Co-Repressor 2 , Nuclear Receptor Subfamily 1, Group F, Member 3 , Promoter Regions, Genetic , Receptors, Retinoic Acid/genetics , Receptors, Thyroid Hormone/genetics , Repressor Proteins/metabolism
18.
J Immunol ; 183(1): 129-36, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19535643

ABSTRACT

Dendritic cells are able to take up exogenous Ags and present Ag-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of APCs, has been demonstrated to target soluble Ags exclusively toward cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model Ag OVA. We could demonstrate both in vitro and in vivo that activation of PPARgamma resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARgamma in dendritic cells induced up-regulation of the coinhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8(+) T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARgamma which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune responses, e.g., in T cell-mediated autoimmunity.


Subject(s)
Antigen Presentation/immunology , B7-1 Antigen/biosynthesis , Cross-Priming/immunology , Membrane Glycoproteins/biosynthesis , PPAR gamma/metabolism , Up-Regulation/immunology , Animals , B7-1 Antigen/genetics , B7-1 Antigen/physiology , B7-H1 Antigen , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cells, Cultured , Coculture Techniques , Dendritic Cells/immunology , Dendritic Cells/metabolism , Immune Tolerance/genetics , Lectins, C-Type/biosynthesis , Lectins, C-Type/genetics , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mannose Receptor , Mannose-Binding Lectins/biosynthesis , Mannose-Binding Lectins/genetics , Membrane Glycoproteins/genetics , Membrane Glycoproteins/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Ovalbumin/immunology , Ovalbumin/metabolism , PPAR gamma/deficiency , PPAR gamma/genetics , Peptides/genetics , Peptides/physiology , Receptors, Antigen, T-Cell/genetics , Receptors, Cell Surface/biosynthesis , Receptors, Cell Surface/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Up-Regulation/genetics
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