Department of Autoimmunity Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Department of Rheumatology, University Hospital Basel, Basel, Switzerland.
JCI Insight. 2022 Jul 8;7(13):e149825. doi: 10.1172/jci.insight.149825.
IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type-specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1β or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1β-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.
白细胞介素 1 受体激活激酶 1（IRAK1）参与许多 TLR 和 IL-1R 下游的信号转导。其作为慢性炎症性疾病药物靶点的潜力尚未得到充分认识。为了研究其在关节炎症中的功能作用，我们生成了一种表达功能性失活 IRAK1（IRAK1 激酶缺陷，IRAK1KD）的小鼠模型，该模型还显示出 IRAK1 蛋白表达和 TLR 信号的细胞类型特异性缺陷减少。关节炎的血清转移模型揭示了 IRAK1 通过其在非造血细胞中的活性对疾病发展和中性粒细胞趋化作用的潜在新作用。一致地，IRAK1KD 滑膜成纤维细胞在受到 IL-1β 或来自类风湿关节炎（RA）和痛风患者的人滑膜液刺激后，中性粒细胞趋化因子趋化因子的分泌减少。与 RA 患者的滑膜衬里成纤维细胞中明显表达 IRAK1 一起，这些数据表明靶向 IRAK1 可能具有治疗益处。由于 IRAK1 激酶活性的药理学抑制对来自小鼠和 RA 患者的滑膜成纤维细胞仅具有轻微作用，因此靶向 IRAK1 的降解可能是首选的药理学模式。总的来说，这些数据将 IRAK1 定位为关节中 IL-1β 依赖性局部炎症环境的核心调节剂和炎症性关节炎的潜在治疗靶标。
