Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Cell Death Dis. 2023 Sep 14;14(9):608. doi: 10.1038/s41419-023-06126-y.
Chemokines secreted by dendritic cells (DCs) play a key role in the regulation of inflammation and autoimmunity through chemokine receptors. However, the role of chemokine receptor CXCR1 in inflammation-inducing experimental autoimmune encephalomyelitis (EAE) and acute respiratory distress syndrome (ARDS) remains largely enigmatic. Here we reported that compared with healthy controls, the level of CXCR1 was aberrantly increased in multiple sclerosis (MS) patients. Knockout of CXCR1 not only ameliorated disease severity in EAE mice but also suppressed the secretion of inflammatory factors (IL-6/IL-12p70) production. We observed the same results in EAE mice with DCs-specific deletion of CXCR1 and antibody neutralization of the ligand CXCL5. Mechanically, we demonstrated a positive feedback loop composed of CXCL5/CXCR1/HIF-1α direct regulating of IL-6/IL-12p70 production in DCs. Meanwhile, we found CXCR1 deficiency in DCs limited IL-6/IL-12p70 production and lung injury in LPS-induced ARDS, a disease model caused by inflammation. Overall, our study reveals CXCR1 governs DCs-mediated inflammation and autoimmune disorders and its potential as a therapeutic target for related diseases.
树突状细胞（DCs）分泌的趋化因子通过趋化因子受体在炎症和自身免疫的调节中发挥关键作用。然而，趋化因子受体 CXCR1 在诱导实验性自身免疫性脑脊髓炎（EAE）和急性呼吸窘迫综合征（ARDS）中的作用在很大程度上仍是个谜。在这里，我们报告称，与健康对照组相比，多发性硬化症（MS）患者的 CXCR1 水平异常升高。CXCR1 敲除不仅改善了 EAE 小鼠的疾病严重程度，还抑制了炎症因子（IL-6/IL-12p70）的分泌。我们在具有 DC 特异性 CXCR1 缺失的 EAE 小鼠和 CXCL5 配体的抗体中和中观察到了相同的结果。在机制上，我们证明了由 CXCL5/CXCR1/HIF-1α 直接调节 DC 中 IL-6/IL-12p70 产生的正反馈环。同时，我们发现 DC 中 CXCR1 的缺失限制了 LPS 诱导的 ARDS 中 IL-6/IL-12p70 的产生和肺损伤，ARDS 是一种由炎症引起的疾病模型。总的来说，我们的研究揭示了 CXCR1 控制 DC 介导的炎症和自身免疫性疾病，以及其作为相关疾病治疗靶点的潜力。
