The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1β. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1β and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.

白细胞介素 1 (IL-1)通路通过 1 型 IL-1 受体 (IL-1R1) 发出信号，并成为全身炎症的中心介质。IL-1 信号传导异常会导致一系列自身炎症性疾病。在这里，我们在一名慢性复发性多灶性骨髓炎(CRMO) 患者中发现了 IL-1R1 (p.Lys131Glu) 的从头错义变异。患者 PBMC显示出强烈的炎症特征，特别是在单核细胞和中性粒细胞。p.Lys131Glu 取代影响了一个关键的带正电荷的氨基酸，从而破坏了拮抗剂配体 IL-1Ra 的结合，但不破坏 IL-1α 或 IL-1β 的结合。这导致 IL-1 信号传导不受阻碍。具有同源突变的小鼠表现出类似的过度炎症和对胶原抗体诱导的关节炎的更易感性，并伴有病理性破骨细胞生成。利用突变的生物学原理，我们设计了一种 IL-1 治疗剂，它可以捕获 IL-1β 和 IL-1α，但不能捕获 IL-1Ra。总的来说，这项工作提供了分子见解和一种潜在的药物，可以提高治疗 IL-1 驱动的疾病的效力和特异性。