IL-36 cytokines and gut immunity

摘要 克罗恩病和溃疡性结肠炎是炎症性肠病(IBD)的两种最常见形式，影响 美国大约有150万人。炎症性肠病的病因尚不清楚，尽管调控失调。 针对微生物区系的先天和获得性免疫反应被认为是疾病的基础 发病机制。目前，针对促炎细胞因子的生物疗法，如肿瘤坏死因子和IL-12/23 展现出了巨大的希望。然而，关于免疫细胞和因子仍有许多需要了解的地方 为IBD作出贡献，以及如何控制它们以改善人类健康。我们最近的工作，资金来自 2018年，本申请寻求建立在此基础上，揭示了IL- 36/IL-36受体(IL-36R)轴在调节先天性和获得性粘膜免疫反应及肠道中的作用 发炎。我们首次报道了IL-36配体在急性和慢性实验中的表达 小鼠结肠炎和人类IBD期间。我们已经证明，IL-36配体，特别是IL-36G，是由 炎性巨噬细胞对小鼠肠道屏障损伤的反应。病毒的生物学后果 在急性肠道损伤期间通过IL-36R发出信号，这可能是IL-1相关的细胞因子轴的预期， 包括炎症增强。值得注意的是，我们观察到，IL-36R信号也需要在 急性结肠损伤的缓解阶段以获得最佳的中性粒细胞募集和IL-23/IL-22的表达。这些 结果使我们得出结论，IL-36/IL-36R轴不仅调节免疫细胞的募集和炎症， 而且还有与IL-22和抗菌肽有关的保护性修复过程。因此，我们推测 炎症和屏障保护紧密交织在一起。超越先天免疫反应，信号 通过IL-36R对CD4+T细胞也有很强的作用。我们发表的研究表明，IL-36配体 有效抑制诱导的调节性T细胞(ITreg)途径，同时增强效应器Th 回应。我们的研究表明Th的严重程度降低了，这证明了这些发现与体内的相关性 IL-36R或IL-36G缺陷小鼠的细胞依赖性恶唑酮结肠炎。总体而言，我们的发现突出了背景- IL-36/IL-36R途径在肠道中的致病和保护作用我们的新产品 初步数据表明：1)在无菌小鼠的急性屏障损伤过程中，IL-36G不被诱导； 可以在体外被细菌配体诱导；2)IL-36R缺陷的微生物区系组成发生了变化 3)T细胞和树突状细胞IL-36R的表达 细胞参与增强炎症信号；4)炎症细胞因子可以被特异性地抑制。 利用负载siRNA的纳米颗粒在肠道中的细胞，同时传递修复因子 比如IL-22。这些数据为进一步研究这一令人兴奋和重要的研究领域奠定了基础。

Abstract Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease (IBD), affect approximately 1.5 million people in the United States. The etiology of IBD remains unclear, however dysregulated innate and adaptive immune responses directed towards the microbiota are believed to underlie disease pathogenesis. Currently biologic therapies targeting pro-inflammatory cytokines such as TNF and IL-12/23 have shown great promise. However, much remains to be understood regarding the immune cells and factors that contribute to IBD and how they can be controlled to improve human health. Our recent work, funded through 2018, which this application seeks to build upon, has unraveled important and complex contributions of the IL- 36/IL-36 receptor (IL-36R) axis in the regulation of innate and adaptive mucosal immune responses and intestinal inflammation. We were the first to report that IL-36 ligands are expressed during acute and chronic experimental colitis in mice and during human IBD. We have shown that IL-36 ligands, particularly IL-36g, are secreted by inflammatory macrophages in response to intestinal barrier damage in mice. The biological consequences of signaling through IL-36R during acute intestinal damage, as might be expected of an IL-1-related cytokine axis, include enhanced inflammation. Strikingly, we observed that IL-36R signaling is also required during the resolution phase of acute colonic injury for optimal neutrophil recruitment and IL-23/IL-22 expression. These results led us to conclude that the IL-36/IL-36R axis regulates not only immune cell recruitment and inflammation, but also protective repair processes that are linked to IL-22 and anti-microbial peptides. Thus, we speculate that inflammation and barrier protection are intimately intertwined. Beyond innate immune responses, signaling through IL-36R also has potent effects on CD4+ T cells. Our published work has demonstrated that IL-36 ligands potently inhibit the induced regulatory T cell (iTreg) pathway, while concomitantly augmenting effector Th responses. The in vivo relevance of these findings is evidenced by our studies showing reduced severity of Th cell-dependent oxazolone colitis in mice deficient in IL-36R or IL-36g. Collectively, our findings highlight context- dependent pathogenic and protective contributions of the IL-36/IL-36R pathway in the intestine. Our new preliminary data demonstrate that: 1) IL-36g is not induced during acute barrier damage in germ-free mice and can be induced in vitro by bacterial ligands; 2) The composition of the microbiota is altered in IL-36R-deficient mice both in the steady-state and following acute barrier damage; 3) IL-36R expression by T cells and dendritic cells is involved in augmenting inflammatory signaling; and 4) Inflammatory cytokines can be inhibited in specific cells in the intestine using siRNA-loaded nanoparticles while simultaneously delivering pro-restitutive factors such as IL-22. These data set the stage for further investigation into this exciting and important area of research.