Portal de Periódicos da CAPES

Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease

2019; Cell Press; Volume: 180; Issue: 1 Linguagem: Inglês

10.1016/j.cell.2019.11.026

1097-4172

June‐Yong Lee, Jason A. Hall, Lina Kroehling, Lin Wu, Tariq Ahmad Najar, Henry H. Nguyen, Woan-Yu Lin, Stephen T. Yeung, Hernandez Moura Silva, Dayi Li, Ashley M. Hine, P’ng Loke, David Hudesman, Jérôme C. Martin, Ephraim Kenigsberg, Miriam Mérad, Kamal M. Khanna, Dan R. Littman,

Immunodeficiency and Autoimmune Disorders

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 RORγt-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.