Differential role of MyD88 and TRIF signaling in myeloid cells in the pathogenesis of autoimmune diabetes

Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic beta cells. While the role of adaptive immunity has been extensively studied, the role of innate immune responses and particularly of Toll- like Receptor (TLR) signaling in T1D remains poorly understood. Here we show that myeloid cell-specific MyD88 deficiency considerably protected mice from the development of streptozotocin (STZ)-induced diabetes. The protective effect of MyD88 deficiency correlated with increased expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in pancreatic lymph nodes from STZ-treated mice and in bone marrow-derived dendritic cells (BMDC) stimulated with apoptotic cells. Mice with myeloid cell specific TIR-domain-containing adapter-inducing interferon-β (TRIF) knockout showed a trend towards accelerated onset of STZ-induced diabetes, while TRIF deficiency resulted in reduced IDO expression in vivo and in vitro. Moreover, myeloid cell specific MyD88 deficiency delayed the onset of diabetes in Non-Obese Diabetic (NOD) mice, whereas TRIF deficiency had no effect. Taken together, these results identify MyD88 signaling in myeloid cells as a critical pathogenic factor in autoimmune diabetes, which is antagonized by TRIF-dependent responses. This differential function of MyD88 and TRIF depends at least in part on their opposite effects in regulating IDO expression in phagocytes exposed to apoptotic cells.

1型糖尿病（Type 1 diabetes, T1D）是由产胰岛素的胰腺β细胞发生自身免疫性破坏所导致的疾病。尽管适应性免疫的作用已被广泛研究，但固有免疫应答，尤其是Toll样受体（Toll-like Receptor, TLR）信号通路在1型糖尿病中的作用仍不甚明确。本研究表明，髓系细胞特异性MyD88缺陷可显著保护小鼠免受链脲佐菌素（streptozotocin, STZ）诱导的糖尿病侵袭。MyD88缺陷的保护作用与经STZ处理的小鼠胰腺淋巴结，以及经凋亡细胞刺激的骨髓来源树突状细胞（bone marrow-derived dendritic cells, BMDC）中免疫调节酶吲哚胺2,3-双加氧酶（indoleamine 2,3-dioxygenase, IDO）的表达上调相关。髓系细胞特异性敲除含TIR结构域的接头蛋白诱导干扰素-β（TIR-domain-containing adapter-inducing interferon-β, TRIF）的小鼠，其STZ诱导的糖尿病发病呈现加速趋势；而TRIF缺陷则会在体内外降低IDO的表达。此外，髓系细胞特异性MyD88缺陷可延缓非肥胖糖尿病（Non-Obese Diabetic, NOD）小鼠的糖尿病发病，而TRIF缺陷则无此效果。综上，上述结果证实，髓系细胞中的MyD88信号通路是自身免疫性糖尿病的关键致病因子，其作用可被TRIF依赖的应答所拮抗。MyD88与TRIF的这种功能差异，至少部分取决于它们在调控暴露于凋亡细胞的吞噬细胞中IDO表达时所产生的相反效应。