Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

ABSTRACTPathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.Graphical AbstractDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE)Dectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cellsOsmR signaling in astrocytes limits EAE progression and promotes remissionNon-canonical Card9-independent signaling drives a distinct Dectin-1-mediated transcriptional program to induce expression of Osm and other factors with protective or anti-inflammatory functions

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Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

Journal of Neuroinflammation ◽

10.1186/s12974-021-02076-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Lin Luo ◽

Xianzhen Hu ◽

Michael L. Dixon ◽

Brandon J. Pope ◽

Jonathan D. Leavenworth ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Myeloid Cells ◽

Autoimmune Encephalomyelitis ◽

Gm Csf ◽

Cns Autoimmunity ◽

The Impact ◽

Experimental Autoimmune

Abstract Background Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

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Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis

Neurotherapeutics ◽

10.1007/s13311-021-01016-7 ◽

2021 ◽

Author(s):

Laura Calvo-Barreiro ◽

Herena Eixarch ◽

Thais Cornejo ◽

Carme Costa ◽

Mireia Castillo ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Therapeutic Effect ◽

Clinical Effect ◽

Short Chain Fatty Acid ◽

Human Gut ◽

Autoimmune Encephalomyelitis ◽

Gut Dysbiosis ◽

Cns Autoimmunity ◽

The Central Nervous System ◽

Experimental Autoimmune

SummaryGut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.

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