Background/Purpose: Interleukin-1 (IL-1) plays a pivotal role in inflammation and immunity. Activation of IL-1 receptor is physiologically inhibited by the IL-1 receptor antagonist (IL-1Ra). Mice lacking the IL-1Ra gene (Il1rn^-/-) are prone to several autoimmune diseases including arthritis; however, the mechanisms by which IL-1Ra provides protection against autoimmune disease remain unknown. Given recent evidence suggesting association of microbiome with autoimmunity, we investigated the role of IL-1Ra in regulation of the intestinal microbiome and the involvement of specific microbiota in development of arthritis.

Methods: Intestinal microbiota were characterized in wild-type and Il1rn^-/- mice using high-throughput 16S rRNA pyrosequencing. Involvement of (intestinal) microbiota in arthritis dvelopment was investigated in germ-free (GF) mice and using oral broad-spectrum and selective antibiotic treatments combined with re-colonization with specific commensals. Intestinal T cell differentiation was assessed by multicolor flow cytometry on lamina propria (LP) mononuclear cells to evaluate potential correlations with arthritis. Cytokine production was determined in supernatants of LP, spleen and lymph node cells cultured with phorbol myristate acetate/ionomycin and preparations of fecal microbiota.

Results: Sequencing data showed that IL-1Ra critically maintains the diversity and the homeostatic composition of intestinal microbiota in mice. IL-1Ra deficiency caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. These alterations potentiated T helper 17 (Th17), but not Th1 and regulatory T cell, differentiation in intestinal lamina propria (LP). Notably, the increased LP Th17 proportion was observed in the absence of the major previously described Th17 inducers segmented filamentous bacteria (SFB). Importantly, LP Th17 expansion preceded the development and positively correlated with the severity of arthritis. The disease was markedly suppressed under germ-free condition, paralleled by a significant and specific reduction of IL-17 production in LP, spleen and lymph nodes draining the inflamed joints. Inhibition of arthritis was also achieved upon short-term treatment with broad-spectrum oral antibiotics. Interestingly, this protection was reversed by specific Th17, but not Th1, induction in LP upon colonization with SFB. In conventional Il1rn^-/-mice lacking SFB, indigenous Gram-negative microbiota were surprisingly identified as disease inducers. Ablation of both IL-1Ra and Toll-like receptor 4 (TLR4) recognizing Gram-negative bacteria revealed that microbial TLR4 activation mediates intestinal and systemic Th17 differentiation and promotes arthritis by inducing mucosal IL-1β, TNFα and IL-23 while leaving IL-6 unaffected.

Conclusion: These findings outline a fascinating regulatory interplay between IL-1Ra, commensal microbiota, TLR4 and Th17 differentiation in the context of autoimmune arthritis. The data suggest a potential role for intestinal microbial TLR4 activation in the development of arthritis in addition to its previously described activation by endogenous agonists.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-1-receptor-antagonist-maintains-intestinal-microbial-homeostasis-to-prevent-overt-toll-like-receptor-4-dependent-intestinal-th17-differentiation-and-autoimmune-arthritis/