MiR‐409‐3p and MiR‐1896 co‐operatively participate in IL‐17‐induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling

Abstract

Th17 cells and interleukin‐17 (IL‐17) have been found to play an important role in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Response to IL‐17, reactive astrocytes accompany with immune cells infiltration and axonal damage in MS/EAE. However, the role and the regulatory mechanism of IL‐17‐activated astrocytes in inflammation and in the EAE process still remain largely unknown. Here, we elucidated that miR‐409‐3p and miR‐1896, as co‐upregulated microRNAs in activated astrocytes and in EAE mice, targeted suppressor of cytokine signaling proteins 3 (SOCS3). Overexpression of miR‐409‐3p or miR‐1896 significantly reduced SOCS3 expression and increased phosphorylation of STAT3 as well as induced the inflammatory cytokines production (IL‐1β, IL‐6, IP‐10, MCP‐1, and KC), CD4+T cells migration and demyelination, in turn aggravating EAE development. Importantly, the effects of co‐overexpression of miR‐409‐3p and miR‐1896 in vitro or in vivo are strongly co‐operative. In contrast, simultaneously silenced miR‐409‐3p and miR‐1896 co‐operatively ameliorates inflammation and demyelination in the central nervous system of EAE mice. Collectively, our findings highlight that miR‐409‐3p and miR‐1896 co‐ordinately promote the production of inflammatory cytokines in reactive astrocytes through the SOCS3/STAT3 pathway and enhance reactive astrocyte‐directed chemotaxis of CD4+T cells, leading to aggravate pathogenesis in EAE mice. Co‐inhibition of miR‐409‐3p and miR‐1896 may be a therapeutic target for treating MS and neuroinflammation.

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

“…For example, overexpression of miR-384 that targets Socs3 resulted in exacerbated EAE and increased Th17 differentiation, while inhibition of miR-384 reversed these changes [99]. Overexpression of miR-409-3p or miR-1896 reduced Socs3 expression and increased phosphorylation of STAT3 in astrocytes in the EAE model, while the silencing of both miRNAs reduced central nervous system inflammation and demyelination [100]. Additionally, the Leukemia inhibitory factor (Lif) was shown to induce Socs3 expression in Th17 cells and to block Jak2 activation and STAT3 phosphorylation.…”

Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases

“…In primary astrocytes, IL-17A induces the expression of MIP-1α (Yi et al, 2014 ). Furthermore, miRNAs are involved in the pathogenesis mediated by IL-17A-expressing astrocytes in EAE (Liu X. et al, 2014 , 2019 ; Shan et al, 2017 ). Under IL-17A stimulation, miRNAs participate in inflammatory cytokine production in astrocytes and, in turn, aggravate EAE development.…”

“…MiR-409-3p and MiR-1896 are involved in the process of IL-17A-mediated secretion of inflammatory cytokines by astrocytes by targeting the SOCS3/STAT3 signaling pathway in EAE mice. Under IL-17A stimulation, miR-873 participates in inflammatory cytokine production in astrocytes through the A20/NF-KB pathway in EAE mice (Liu X. et al, 2014 ; Shan et al, 2017 ; Liu X. et al, 2019 ). In EAE mice, proinflammatory gene expression induced by IL-17A is diminished through the abrogation of p38α in astrocytes, which was via the defective activation of MAPK-activated protein kinase 2 (Huang et al, 2015 ).…”

miR-409-3p is reduced in plasma and islet immune infiltrates of NOD diabetic mice and is differentially expressed in people with type 1 diabetes

“…Recent studies have highlighted the importance of miRNAmediated regulation of transcription factors, immune checkpoints and metabolism-triggered molecules during the differentiation of various immune-cell subsets [42][43][44][45]. In detail, Socs3 (suppressor of cytokine signalling 3) is a direct target of miR-409-3p and is involved in the differentiation of CD8 + T cells [46]. Cpt1a, a previously demonstrated regulator of memory CD8 + T cell lipid metabolism and immune response in autoimmune diseases [47], is a conserved predicted target of miR-409-3p.…”