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Background & Aims: Interferon regulatory factor 3 (IRF3) is a transcription factor mediating anti-viral responses, yet recent evidence indicates that IRF3 also has critical non-transcriptional functions, including activating RIG-I-like receptors-induced IRF-3-mediated pathway of apoptosis (RIPA) and restricting activity of NFκB Using a novel murine model expressing only nontranscriptional IRF3 activity (Irf3 S1/S1), we tested the hypothesis that non-transcriptional functions of IRF3 modulate innate immune responses in the Gao-binge (acute on chronic) model of alcoholrelated liver disease. Methods: C57BL/6, Irf3 −/− and Irf3 S1/S1 were exposed to Gao-binge ethanol-induced liver injury. IRF3-mediated RIPA was investigated in cultured macrophages. Results: Phospho-IRF3 and IRF3-mediated signals were elevated in livers of patients with alcoholic hepatitis. In C57BL/6 mice, Gao-binge ethanol exposure activated IRF3 signaling and resulted in hepatocellular injury. Indicators of liver injury were differentially impacted by Irf3

Chronic inflammation is a common feature of obesity with elevated cytokines such as Interleukin-1 (IL-1) in circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2-Myddosome to mitochondria outer membrane via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membrane to suppress oxidative phosphorylation and fatty acid oxidation, thereby, attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high fat diet (HFD)-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced HFD-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

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Increasing evidence suggests that intratumoral inflammation has an outsized influence on antitumor immunity. Here, we report that IL-17, a proinflammatory cytokine widely associated with poor prognosis in solid tumors, drives the therapeutic failure of anti–PD-L1. By timing the deletion of IL-17 signaling specifically in cancer-associated fibroblasts (CAFs) in late-stage tumors, we show that IL-17 signaling drives immune exclusion by activating a collagen deposition program in murine models of cutaneous squamous cell carcinoma (cSCC). Ablation of IL-17 signaling in CAFs increased the infiltration of cytotoxic T cells into the tumor mass and sensitized otherwise resistant cSCC to anti–PD-L1 treatment. Mechanistically, the collagen deposition program in CAFs was driven by IL-17–induced translation of HIF1α, which was mediated by direct binding of Act1, the adaptor protein of IL-17 receptor, to a stem-loop structure in the 3′ untranslated region (UTR) in Hif1α mRNA. Disruption of Act1’s binding to Hif1α mRNA abolished IL-17–induced collagen deposition and enhanced anti–PD-L1–mediated tumor regression.

The C-type lectin receptor Mincle is known for its important role in innate immune cells in recognizing pathogen and damage associated molecular patterns. Here we report a T cell–intrinsic role for Mincle in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Genomic deletion of Mincle in T cells impairs TH17, but not TH1 cell-mediated EAE, in alignment with significantly higher expression of Mincle in TH17 cells than in TH1 cells. Mechanistically, dying cells release β-glucosylceramide during inflammation, which serves as natural ligand for Mincle. Ligand engagement induces activation of the ASC-NLRP3 inflammasome, which leads to Caspase8-dependent IL-1β production and consequentially TH17 cell proliferation via an autocrine regulatory loop. Chemical inhibition of β-glucosylceramide synthesis greatly reduces inflammatory CD4+ T cells in the central nervous system and inhibits EAE progression in mice. Taken together, this study indicates that sensing of danger signals by Mincle on TH17 cells plays a critical role in promoting CNS inflammation.

Toll-like receptors/Interleukin-1 receptor signaling plays an important role in high-fat diet-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduces high-fat diet-induced body weight gain, increases whole body energy expenditure and improves insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induces the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuates high-fat diet-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a potential therapeutic target for obesity.