Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cell Rep. 2022 Mar 15;38(11):110520. doi: 10.1016/j.celrep.2022.110520.
RAR-related orphan receptor-γ (RORγt) is an essential transcription factor for thymic T cell development, secondary lymphoid tissue organogenesis, and peripheral immune cell differentiation. Serine 182 phosphorylation is a major post-translational modification (PTM) on RORγt. However, the in vivo contribution of this PTM in health and disease settings is unclear. We report that this PTM is not involved in thymic T cell development and effector T cell differentiation. Instead, it is a critical regulator of inflammation downstream of IL-1β signaling and extracellular signal regulated kinases (ERKs) activation. ERKs phosphorylation of serine 182 on RORγt serves to simultaneously restrict Th17 hyperactivation and promote anti-inflammatory cytokine IL-10 production in RORγt Treg cells. Phospho-null RORγt knockin mice experience exacerbated inflammation in models of colitis and experimental autoimmune encephalomyelitis (EAE). In summary, the IL-1β-ERK-RORγt circuit protects against T cell-mediated inflammation and provides potential therapeutic targets to combat autoimmune diseases.
RAR 相关孤儿受体-γ（RORγt）是胸腺 T 细胞发育、次级淋巴组织器官发生和外周免疫细胞分化所必需的转录因子。丝氨酸 182 磷酸化是 RORγt 的主要翻译后修饰（PTM）之一。然而，在健康和疾病状态下，这种 PTM 的作用尚不清楚。我们报告称，这种 PTM 不参与胸腺 T 细胞发育和效应 T 细胞分化。相反，它是 IL-1β 信号和细胞外信号调节激酶（ERK）激活下游炎症的关键调节剂。ERK 对 RORγt 丝氨酸 182 的磷酸化可同时限制 Th17 过度激活并促进 RORγt Treg 细胞中抗炎细胞因子 IL-10 的产生。磷酸化缺失的 RORγt 敲入小鼠在结肠炎和实验性自身免疫性脑脊髓炎（EAE）模型中经历了更严重的炎症。总之，IL-1β-ERK-RORγt 通路可防止 T 细胞介导的炎症，并为治疗自身免疫性疾病提供了潜在的治疗靶点。
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