Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
Center for Diagnostics and Therapeutics, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5076-E5085. doi: 10.1073/pnas.1718902115. Epub 2018 May 14.
The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ-induced IL-23 required Notch2-dependent (CD11bCD103) dendritic cells (DCs), but not Batf3-dependent (CD11bCD103) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36γ-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.
肠道上皮细胞的作用是将宿主免疫细胞与不受限制的微生物群和其他环境刺激隔离开来。当肠道上皮细胞受损或功能失调时，免疫细胞被激活以产生白细胞介素（IL）-22，它参与了屏障表面的修复和保护。然而，导致肠道组织损伤后产生 IL-22 和相关抗菌肽（AMP）的具体途径仍不完全清楚。在这里，我们定义了一个关键的 IL-36/IL-23/IL-22 细胞因子网络，该网络对于 AMP 产生和宿主防御至关重要。使用肠道损伤和修复的小鼠模型，我们表明 IL-36γ 是体外和体内 IL-23 的有效诱导剂。IL-36γ 诱导的 IL-23 需要 Notch2 依赖性（CD11bCD103）树突状细胞（DC），但不需要 Batf3 依赖性（CD11bCD103）DC 或 CSF1R 依赖性巨噬细胞。将 IL-36 受体（IL-36R）与 DC 产生 IL-23 联系起来的细胞内信号级联涉及 MyD88 和 NF-κB 亚基 c-Rel 和 p50。与体外观察结果一致，IL-36R 和 IL-36γ 缺陷小鼠表现出明显降低的 IL-23、IL-22 和 AMP 水平，因此无法从急性肠道损伤中恢复。有趣的是，缺乏 IL-36R 或 IL-36γ 的小鼠的恢复可以通过用外源性 IL-23 治疗来挽救。这种恢复伴随着结肠中 IL-22 和 AMP 表达的恢复。总的来说，这些数据定义了一个涉及 IL-36γ、IL-23 和 IL-22 的细胞因子网络，该网络在肠道屏障损伤时被激活，并参与提供关键的宿主防御。
