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， 在美国大约有150万人。IBD的病因尚不清楚，但失调 针对微生物群的先天性和适应性免疫反应被认为是疾病的基础 发病机制目前，靶向促炎细胞因子如TNF和IL-12/23的生物疗法具有以下优点： 显示出巨大的潜力。然而，关于免疫细胞和因子， 有助于IBD以及如何控制它们以改善人类健康。我们最近的工作，通过资助 2018年，本申请寻求建立在此基础上，已经揭示了IL的重要和复杂的贡献， IL-36/IL-36受体（IL-36 R）轴在调节先天性和适应性粘膜免疫应答和肠 炎症我们是第一个报道IL-36配体在急性和慢性实验性肝损伤中表达的人。 小鼠和人IBD期间的结肠炎。我们已经表明，IL-36配体，特别是IL-36 g，是由 炎症巨噬细胞对小鼠肠屏障损伤的反应。的生物学后果 在急性肠损伤期间通过IL-36 R的信号传导，如IL-1相关细胞因子轴所预期的， 包括增强炎症。引人注目的是，我们观察到IL-36 R信号传导也是在细胞凋亡过程中所必需的。 最佳中性粒细胞募集和IL-23/IL-22表达的急性结肠损伤的消退期。这些 结果使我们得出结论：IL-36/IL-36 R轴不仅调节免疫细胞募集和炎症， 还包括与IL-22和抗菌肽相关的保护性修复过程。因此，我们推测， 炎症和屏障保护密切相关。除了先天免疫反应， 通过IL-36 R对CD 4 + T细胞也有有效的作用。我们已发表的工作表明，IL-36配体 有效抑制诱导的调节性T细胞（iTreg）通路，同时增加效应Th细胞 应答我们的研究表明，Th细胞亚群的严重程度降低， IL-36 R或IL-36 g缺陷小鼠的细胞依赖性恶唑酮结肠炎。总的来说，我们的发现突出了背景- 肠中IL-36/IL-36 R途径的依赖性致病和保护作用。我们的新 初步数据表明：1）在无菌小鼠中急性屏障损伤期间不诱导IL-36 g， 可以在体外由细菌配体诱导; 2）在IL-36 R缺陷的小鼠中， 在稳态和急性屏障损伤后的小鼠中; 3）T细胞和树突状细胞的IL-36 R表达 细胞参与增强炎症信号传导;和4）炎性细胞因子可以被特异性地抑制， 使用装载siRNA的纳米颗粒同时递送促恢复因子 例如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.