Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (T H 17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1β (IL-1β) induced a signal transducer and activator of transcription 5 (STAT5)–mediated steroid-resistant transcriptional program in T H 17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. T H 17-specific deletion of STAT5 ablated the IL-1β–induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1β synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)–resident CD69 + T H 17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident T H 17 cells, reduced EAE severity, and prevented relapse. CD69 + tissue-resident T H 17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1β–STAT5 signaling in T H 17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in T H 17-mediated CNS autoimmunity.

中文翻译：

---

ATH 17 内在 IL-1β-STAT5 轴驱动自身免疫性神经炎症中的类固醇抵抗

类固醇耐药对自身免疫性神经炎症的治疗提出了重大挑战。 T 助手 17 (TH17) 细胞广泛参与类固醇抵抗的病理学；然而，其根本机制尚不清楚。在这项研究中，我们发现白介素 1 受体 (IL-1R) 阻断可使实验性自身免疫性脑脊髓炎 (EAE) 小鼠对地塞米松 (Dex) 治疗敏感。白细胞介素-1β (IL-1β) 在 T 细胞中诱导信号转导子和转录激活子 5 (STAT5) 介导的类固醇抗性转录程序H17 细胞，促进炎症细胞因子的产生并抑制 Dex 诱导的抗炎基因。时间HSTAT5 17 特异性缺失消除了 IL-1β 诱导的类固醇抗性转录程序，并使 EAE 小鼠对 Dex 治疗敏感。 IL-1β与Dex协同促进CD69的STAT5依赖性表达和中枢神经系统（CNS）驻留CD69的发育+时间H17 个细胞。 IL-1R 阻断和 Dex 联合治疗可消除 CNS 驻留 TH17 细胞，降低 EAE 严重程度，并防止复发。 CD69+组织驻留TH在多发性硬化症患者的脑损伤中也检测到了 17 个细胞。这些发现 (i) 表明 T 细胞中的 IL-1β–STAT5 信号传导H17 细胞介导类固醇抵抗，并 (ii) 确定逆转 T 细胞类固醇抵抗的治疗策略H17 介导的中枢神经系统自身免疫。