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 美国约有 150 万人。 IBD 的病因仍不清楚，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根源 发病机制。目前针对促炎细胞因子（例如 TNF 和 IL-12/23）的生物疗法已 显示出了巨大的希望。然而，关于免疫细胞和因素仍有很多需要了解。 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 该应用程序试图建立在 2018 年基础上，它揭示了 IL- 的重要而复杂的贡献 36/IL-36 受体 (IL-36R) 轴在调节先天性和适应性粘膜免疫反应以及肠道中的作用 炎症。我们是第一个报道IL-36配体在急性和慢性实验过程中表达的 小鼠结肠炎和人类 IBD 期间的结肠炎。我们已经证明 IL-36 配体，特别是 IL-36g，是由 炎症巨噬细胞对小鼠肠道屏障损伤的反应。的生物学后果 急性肠道损伤期间通过 IL-36R 发出信号，正如 IL-1 相关细胞因子轴所预期的那样， 包括炎症增强。引人注目的是，我们观察到 IL-36R 信号传导在 急性结肠损伤的缓解阶段，以实现最佳中性粒细胞募集和 IL-23/IL-22 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募集和炎症， 还包括与 IL-22 和抗微生物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。除了先天免疫反应之外，信号传导 IL-36R 对 CD4 T 细胞也有有效作用。我们发表的工作表明 IL-36 配体 有效抑制诱导性调节性 T 细胞 (iTreg) 通路，同时增强效应 Th 回应。我们的研究证明了这些发现的体内相关性，显示 Th 的严重程度降低 IL-36R 或 IL-36g 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—— 肠道中 IL-36/IL-36R 通路的依赖性致病和保护作用。我们的新 初步数据表明：1）在无菌小鼠的急性屏障损伤期间不会诱导IL-36g，并且 可以在体外被细菌配体诱导； 2) IL-36R 缺陷时微生物群的组成发生改变 处于稳态和急性屏障损伤后的小鼠； 3) T细胞和树突状细胞表达IL-36R 细胞参与增强炎症信号传导； 4) 可以在特定情况下抑制炎症细胞因子 使用负载 siRNA 的纳米颗粒，同时递送促恢复因子的肠道细胞 例如IL-22。这些数据为进一步研究这一令人兴奋且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.