Departments of Ophthalmology and Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.
Invest Ophthalmol Vis Sci. 2021 May 3;62(6):10. doi: 10.1167/iovs.62.6.10.
Interleukin (IL)-36 cytokines have been shown to play either beneficial or detrimental roles in the infection of mucosal tissues in a pathogen-dependent manner, but their involvement in fungal keratitis remains elusive. We herein investigated their expression and function in mediating corneal innate immunity against Candida albicans infection.
Gene expression in mouse corneas with or without C. albicans infection was determined by regular RT- and real-time (q)-PCR, Western blot analysis, ELISA or proteome profile assay. The severity of C. albicans keratitis was assessed using clinical scoring, bacterial counting, and myeloperoxidase (MPO) activity as an indicator of neutrophil infiltration. IL36R knockout mice and IL-33-specific siRNA were used to assess the involvement IL-33 signaling in C. albicans-infected corneas. B6 CD11c-DTR mice and clodronate liposomes were used to define the involvement of dendritic cells (DCs) and macrophages in IL-36R signaling and C. albicans keratitis, respectively.
IL-36γ were up-regulated in C57BL6 mouse corneas in response to C. albicans infection. IL-36 receptor-deficient mice display increased severity of keratitis, with a higher fungal load, MPO, and IL-1β levels, and lower soluble sIL-1Ra and calprotectin levels. Exogenous IL-36γ prevented fungal keratitis pathogenesis with lower fungal load and MPO activity, higher expression of sIL-1Ra and calprotectin, and lower expression of IL-1β, at mRNA or protein levels. Protein array analysis revealed that the expression of IL-33 and REG3G were related to IL-36/IL36R signaling, and siRNA downregulation of IL-33 increased the severity of C. albicans keratitis. Depletion of dendritic cells or macrophages resulted in severe C. albicans keratitis and yet exhibited minimal effects on exogenous IL-36γ-induced protection against C. albicans infection in B6 mouse corneas.
IL-36/IL36R signaling plays a protective role in fungal keratitis by promoting AMP expression and by suppressing fungal infection-induced expression of proinflammatory cytokines in a dendritic cell- and macrophage-independent manner.
白细胞介素 (IL)-36 细胞因子在依赖病原体的方式中在粘膜组织感染中表现出有益或有害的作用，但它们在真菌性角膜炎中的作用仍不清楚。本文研究了它们在介导角膜先天免疫对抗白色念珠菌感染中的表达和功能。
通过常规 RT-PCR 和实时 (q)-PCR、Western blot 分析、ELISA 或蛋白质组谱分析确定有或没有白色念珠菌感染的小鼠角膜中的基因表达。使用临床评分、细菌计数和髓过氧化物酶 (MPO) 活性作为中性粒细胞浸润的指标来评估白色念珠菌角膜炎的严重程度。使用 IL-33 特异性 siRNA 和 IL36R 敲除小鼠来评估 IL-33 信号在感染白色念珠菌的角膜中的作用。使用 B6 CD11c-DTR 小鼠和氯膦酸盐脂质体分别定义树突状细胞 (DC) 和巨噬细胞在 IL-36R 信号和白色念珠菌角膜炎中的作用。
IL-36γ 在 C57BL6 小鼠角膜中响应白色念珠菌感染而上调。IL-36 受体缺陷型小鼠的角膜炎严重程度增加，真菌负荷增加，MPO 和 IL-1β 水平升高，可溶性 sIL-1Ra 和钙卫蛋白水平降低。外源性 IL-36γ 通过降低真菌负荷和 MPO 活性、增加 sIL-1Ra 和钙卫蛋白的表达以及降低 IL-1β 的表达（在 mRNA 或蛋白水平上）来预防真菌性角膜炎的发病机制。蛋白质阵列分析显示，IL-33 和 REG3G 的表达与 IL-36/IL36R 信号有关，并且 siRNA 下调 IL-33 增加了白色念珠菌角膜炎的严重程度。耗尽树突状细胞或巨噬细胞导致严重的白色念珠菌角膜炎，但对 B6 小鼠角膜中外源性 IL-36γ 诱导的抗白色念珠菌感染的保护作用影响最小。
IL-36/IL36R 信号通过促进 AMP 的表达并以树突状细胞和巨噬细胞非依赖性方式抑制真菌感染诱导的促炎细胞因子的表达，在真菌性角膜炎中发挥保护作用。
Zotero 插件
