Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease
Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease
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DOI：
10.1016/j.cell.2019.11.026
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发表时间：
2020-01-09
期刊：
影响因子：
64.5
通讯作者：
Littman, Dan R.
中科院分区：
文献类型：
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作者：
Lee, June-Yong;Hall, Jason A.;Littman, Dan R.
产生白细胞介素（IL）-17细胞因子的类淋巴细胞保护屏障组织免受病原微生物的侵害，但也是炎症和自身免疫性疾病的主要效应物。T辅助17（Th 17）细胞由IL-17 A和IL-17 F的ROR γ t依赖性产生定义，在肠道中从初始CD 4（+）T细胞经微生物群定向分化后发挥稳态功能。在非致病性环境中，它们的细胞因子产生由邻近肠上皮细胞分泌的血清淀粉样蛋白A蛋白（SAA 1和SAA 2）调节。然而，Th 17细胞的行为根据其环境而显著变化。在这里，我们表明，SAA还指导致病性促炎性Th 17细胞分化程序，直接作用于T细胞与STAT 3激活细胞因子的合作。使用功能丧失和获得的小鼠模型，我们表明SAA 1，SAA 2和SAA 3在促进Th 17介导的炎症性疾病中具有不同的全身和局部功能。这些研究表明，由SAA调节的T细胞信号传导途径可能是抗炎治疗的有吸引力的靶点。
Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by ROR gamma t-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4(+) T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.