scholarly journals Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiajia Wang ◽  
Jiaying Wang ◽  
Wenxiang Hong ◽  
Lulu Zhang ◽  
Liqian Song ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Negative Regulation ◽  
Biological Processes ◽  
Dc Functions ◽  
Autoimmune Encephalomyelitis ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
Human And Mouse ◽  
Dc Maturation ◽  
Experimental Autoimmune

AbstractOptineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive. Here we show that OPTN is upregulated in human and mouse DC maturation, and that deletion of Optn in mice via CD11c-Cre attenuates DC maturation and impairs the priming of CD4+ T cells, thus ameliorating autoimmune symptoms such as experimental autoimmune encephalomyelitis (EAE). Mechanistically, OPTN binds to the JH1 domain of JAK2 and inhibits JAK2 dimerization and phosphorylation, thereby preventing JAK2-STAT3 interaction and inhibiting STAT3 phosphorylation to suppress downstream transcription of IL-10. Without such a negative regulation, Optn-deficient DCs eventually induce an IL-10/JAK2/STAT3/IL-10 positive feedback loop to suppress DC maturation. Finally, the natural product, Saikosaponin D, is identified as an OPTN inhibitor, effectively inhibiting the immune-stimulatory function of DCs and the disease progression of EAE in mice. Our findings thus highlight a pivotal function of OPTN for the regulation of DC functions and autoimmune disorders.

scholarly journals NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis

2015 ◽  
Vol 212 (10) ◽  
pp. 1739-1752 ◽  
Author(s):  
Wai Po Chong ◽  
Nicholas van Panhuys ◽  
Jun Chen ◽  
Phyllis B. Silver ◽  
Yingyos Jittayasothorn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Feedback Loop ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Response ◽  
Regulatory Circuit ◽  
Draining Lymph Node ◽  
Ifn Γ ◽  
Necessary And Sufficient ◽  
Experimental Autoimmune

IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ+/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ–IL-27 axis.

scholarly journals The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

scholarly journals Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Catherine H. Poholek ◽  
Itay Raphael ◽  
Dongwen Wu ◽  
Shankar Revu ◽  
Natalie Rittenhouse ◽  
...  
Keyword(s):  
Th17 Cell ◽  
Th17 Cells ◽  
Cytokine Production ◽  
Cell Function ◽  
Autoimmune Encephalomyelitis ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Normal Production ◽  
Experimental Autoimmune

The STAT3 signaling pathway is required for early Th17 cell development, and therapies targeting this pathway are used for autoimmune disease. However, the role of STAT3 in maintaining inflammatory effector Th17 cell function has been unexplored. Th17ΔSTAT3 mice, which delete STAT3 in effector Th17 cells, were resistant to experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Th17 cell numbers declined after STAT3 deletion, corresponding to reduced cell cycle. Th17ΔSTAT3 cells had increased IL-6–mediated phosphorylation of STAT1, known to have antiproliferative functions. Th17ΔSTAT3 cells also had reduced mitochondrial membrane potential, which can regulate intracellular Ca2+. Accordingly, Th17ΔSTAT3 cells had reduced production of proinflammatory cytokines when stimulated with myelin antigen but normal production of cytokines when TCR-induced Ca2+ flux was bypassed with ionomycin. Thus, early transcriptional roles of STAT3 in developing Th17 cells are later complimented by noncanonical STAT3 functions that sustain pathogenic Th17 cell proliferation and cytokine production.

scholarly journals Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 925
Author(s):  
Khalid Alhazzani ◽  
Sheikh F. Ahmad ◽  
Naif O. Al-Harbi ◽  
Sabry M. Attia ◽  
Saleh A. Bakheet ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Cd4 T Cells ◽  
Inflammatory Markers ◽  
Clinical Symptoms ◽  
Autoimmune Encephalomyelitis ◽  
Disease Symptoms ◽  
Stat3 Signaling ◽  
Relapsing Remitting ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.

scholarly journals HMGB1 Promotes the Release of Sonic Hedgehog From Astrocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Yifan Xiao ◽  
Yan Sun ◽  
Wei Liu ◽  
FanFan Zeng ◽  
Junyu Shi ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
High Mobility ◽  
Signal Pathway ◽  
Toll Like Receptor ◽  
Advanced Glycation ◽  
Autoimmune Encephalomyelitis ◽  
Stat3 Phosphorylation ◽  
Glycation End Products ◽  
End Products ◽  
Experimental Autoimmune

High mobility group box 1 protein (HMGB1) is known to be a trigger of inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, it may play a different role in some way. Here we investigated the effect of HMGB1 on promoting sonic hedgehog (shh) release from astrocytes as well as the possible signal pathway involved in it. Firstly, shh increased in astrocytes after administration of recombinant HMGB1 or decreased after HMGB1 was blocked when stimulated by homogenate of the onset stage of EAE. Moreover, the expression of HMGB1 receptors, toll-like receptor (TLR) 2 and receptor for advanced glycation end products (RAGE) increased after HMGB1 administration in primary astrocytes. However, the enhancing effect of HMGB1 on shh release from astrocytes was suppressed only after RAGE was knocked out or blocked. Mechanistically, HMGB1 functioned by activating RAGE-mediated JNK, p38, stat3 phosphorylation. Moreover, HMGB1 could induce shh release in EAE. Additionally, intracerebroventricular injection of recombinant shh protein on the onset stage of EAE alleviated the progress of disease and decreased demylination, compared to the mice with normal saline treatment. Overall, HMGB1 promoted the release of shh from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE, which may provide new insights of HMGB1 function in EAE.

scholarly journals Epigenetic initiation of the TH17 differentiation program is promoted by Cxxc finger protein 1

2019 ◽  
Vol 5 (10) ◽  
pp. eaax1608 ◽  
Author(s):  
Feng Lin ◽  
Xiaoyu Meng ◽  
Yixin Guo ◽  
Wenqiang Cao ◽  
Wanlu Liu ◽  
...  
Keyword(s):  
Autoimmune Encephalomyelitis ◽  
Stat3 Signaling ◽  
Finger Protein ◽  
Genome Wide ◽  
Th17 Differentiation ◽  
Specific Deletion ◽  
Experimental Autoimmune ◽  
Cxxc Finger Protein 1

IL-6/STAT3 signaling is known to initiate the TH17 differentiation program, but the upstream regulatory mechanisms remain minimally explored. Here, we show that Cxxc finger protein 1 (Cxxc1) promoted the generation of TH17 cells as an epigenetic regulator and prevented their differentiation into Treg cells. Mice with a T cell–specific deletion of Cxxc1 were protected from experimental autoimmune encephalomyelitis and were more susceptible to Citrobacter rodentium infection. Cxxc1 deficiency decreased IL-6Rα expression and impeded IL-6/STAT3 signaling, whereas the overexpression of IL-6Rα could partially reverse the defects in Cxxc1-deficient TH17 cells in vitro and in vivo. Genome-wide occupancy analysis revealed that Cxxc1 bound to Il6rα gene loci by maintaining the appropriate H3K4me3 modification of its promoter. Therefore, these data highlight that Cxxc1 as a key regulator governs the balance between TH17 and Treg cells by controlling the expression of IL-6Rα, which affects IL-6/STAT3 signaling and has an impact on TH17-related autoimmune diseases.

scholarly journals Interleukin-26, preferentially produced by TH17 lymphocytes, regulates CNS barrier function

2020 ◽  
Vol 7 (6) ◽  
pp. e870 ◽  
Author(s):  
Bieke Broux ◽  
Stephanie Zandee ◽  
Elizabeth Gowing ◽  
Marc Charabati ◽  
Marc-André Lécuyer ◽  
...  
Keyword(s):  
Immune Cell ◽  
Postmortem Brain ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Lymphocytes ◽  
Postmortem Brain Tissue ◽  
Human And Mouse ◽  
Experimental Autoimmune

ObjectiveTo investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity.MethodsExpression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26–treated human BBB ECs. Myelin oligodendrocyte glycoprotein35–55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry.ResultsIL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs.ConclusionsOur study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

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