An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression
An autonomous activation of interleukin-17 receptor signaling sustains inflammation and promotes disease progression
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DOI：
10.1016/j.immuni.2023.06.012
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发表时间：
2023-09-12
期刊：
影响因子：
32.4
通讯作者：
Xu，Qiang
中科院分区：
文献类型：
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作者：
Luo，Qiong;Liu，Yijun;Xu，Qiang
抗白细胞介素-17（IL-17）治疗已用于各种自身免疫性疾病。然而，在几种IL-17相关疾病中的疗效出乎意料地有限，并且有限疗效的机制仍不清楚。在这里，我们表明，含有衔接分子Act 1和酪氨酸磷酸酶SHP 2的分子复合物介导的自主IL-17 R信号，加速和持续炎症。在各种自身免疫性疾病中异常增强的SHP 2由星形胶质细胞和角质形成细胞中的IL-17 A本身诱导，即使在抗IL-17治疗后也维持趋化因子的产生。从机制上讲，SHP 2直接与Act 1相互作用并使其去磷酸化，后者取代Act 1-TRAF 5复合物并诱导IL-17非依赖性IL-17 R信号转导激活。SHP 2的遗传或药理学失活，或阻断Act 1-SHP 2相互作用，使IL-17诱导的和IL-17非依赖性信号传导瘫痪，并减弱原发性或复发性实验性自身免疫性脑脊髓炎。因此，Act 1-SHP 2复合物介导IL-17 R信号传导自主激活的替代途径，靶向其可能是除当前抗体疗法之外的IL-17相关疾病的治疗选择。
Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.