scholarly journals Deficiency of IκB Kinase β in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis

2016 ◽  
Vol 186 (5) ◽  
pp. 1245-1257 ◽  
Author(s):  
Wenlin Hao ◽  
Yann Decker ◽  
Laura Schnöder ◽  
Andrea Schottek ◽  
Dong Li ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Iκb Kinase ◽  
Experimental Autoimmune

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

2020 ◽  
Author(s):  
M. Elizabeth Deerhake ◽  
Keiko Danzaki ◽  
Makoto Inoue ◽  
Emre D. Cardakli ◽  
Toshiaki Nonaka ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Oncostatin M ◽  
List Type ◽  
Autoimmune Encephalomyelitis ◽  
Protective Function ◽  
Lectin Receptor ◽  
Neurologic Disorders ◽  
Cns Autoimmunity ◽  
Experimental Autoimmune

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

scholarly journals Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming

2017 ◽  
Vol 47 (12) ◽  
pp. 2090-2100 ◽  
Author(s):  
Miriam Fernández ◽  
Eva M. Monsalve ◽  
Susana López-López ◽  
Almudena Ruiz-García ◽  
Susana Mellado ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

scholarly journals IκB Kinase 2/β Deficiency Controls Expansion of Autoreactive T Cells and Suppresses Experimental Autoimmune Encephalomyelitis

2007 ◽  
Vol 179 (1) ◽  
pp. 179-185 ◽  
Author(s):  
Bernhard Greve ◽  
Robert Weissert ◽  
Nada Hamdi ◽  
Estelle Bettelli ◽  
Raymond A. Sobel ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Autoreactive T Cells ◽  
Iκb Kinase ◽  
Experimental Autoimmune

scholarly journals Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis

2017 ◽  
Vol 3 (1) ◽  
pp. 205521731769872 ◽  
Author(s):  
Laura K Green ◽  
Pirooz Zareie ◽  
Nikki Templeton ◽  
Robert A Keyzers ◽  
Bronwen Connor ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Severity ◽  
Glatiramer Acetate ◽  
Atypical Antipsychotic ◽  
Myeloid Cells ◽  
Antipsychotic Agent ◽  
Antipsychotic Agents ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background Atypical antipsychotic agents (AAP) alleviate the symptoms of severe mental health disorders, such as schizophrenia, by antagonizing dopamine and serotonin receptors. Recently, AAP have also been shown to exhibit immunomodulatory properties in the central nervous system (CNS). Objective Building on research which demonstrated the ability of the AAP risperidone and clozapine to modify the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we aimed to more fully investigate the potential of clozapine as a possible treatment for MS. Results We report that orally administered clozapine significantly reduced the disease severity of EAE in a dose-dependent manner and was effective when administered prophylactically and therapeutically. In comparison to risperidone, quetiapine, and olanzapine, clozapine was the best at reducing disease severity. While clozapine-treated mice had only modest changes to peripheral leukocytes and cytokine responses, these animals had significantly fewer CNS-infiltrating CD4 T cells and myeloid cells. Furthermore, the CNS myeloid cells displayed a less activated phenotype in mice treated with clozapine. Finally, we found that co-administration of clozapine with glatiramer acetate enhanced disease protection compared to either treatment alone. Conclusion These studies indicate that clozapine is an effective immunomodulatory agent with the potential to treat immune-mediated diseases such as MS.

scholarly journals Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis

2019 ◽  
Vol 216 (11) ◽  
pp. 2562-2581 ◽  
Author(s):  
Sheng Li ◽  
Yuqing Wu ◽  
Dongxue Yang ◽  
Chunyan Wu ◽  
Chunmei Ma ◽  
...  
Keyword(s):  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
Nlrp3 Inflammasome ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Infiltration ◽  
Secondary Lymphoid Organs ◽  
Experimental Autoimmune

The NLRP3 inflammasome is critical for EAE pathogenesis; however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome, in EAE has not been well defined. Here, we observed that the levels of GSDMD protein were greatly enhanced in the CNS of EAE mice, especially near the areas surrounding blood vessels. GSDMD was required for the pathogenesis of EAE, and GSDMD deficiency in peripheral myeloid cells impaired the infiltration of immune cells into the CNS, leading to the suppression of neuroinflammation and demyelination. Furthermore, the loss of GSDMD reduced the activation and differentiation of T cell in the secondary lymphoid organs and prevented T cell infiltration into CNS of EAE. The administration of inflammasome-related cytokines partially rescued the impairment of pathogenesis of EAE in GSDMD KO mice. Collectively, these findings provide the first demonstration of GSDMD in peripheral myeloid cells driving neuroinflammation during EAE pathogenesis.

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

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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