Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
J Clin Invest. 2021 Sep 15;131(18). doi: 10.1172/JCI141008.
IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.
IL-1β 是一种促炎介质，在先天和适应性免疫中发挥作用。在这里，我们表明，IL-1β 通过诱导 Tregs 的破骨细胞生成能力，导致自身免疫性关节炎。使用通过缺乏白细胞介素-1 受体拮抗剂 (Il1rn-/-) 引起关节炎症的小鼠，我们观察到 IL-1β 阻断在早期关节炎中比在已建立的关节炎中更有效地减轻疾病，特别是在骨侵蚀方面。保护伴随着滑膜 CD4+Foxp3+Tregs 的减少，这些 Tregs 显示出保留的抑制能力和有氧代谢，但 RANKL 的异常表达和驱动 RANKL 依赖性破骨细胞分化的惊人能力。用 IL-1β 分化的 Il1rn-/-Tregs 和野生型 Tregs 在过继转移后加速了骨侵蚀。人类 Tregs 表现出类似的分化，并且可以在类风湿关节炎滑膜组织中鉴定出相应的 RANKLhiFoxp3+T 细胞。这些发现共同确定了 IL-1β 诱导的破骨细胞生成 Tregs 是关节炎中骨侵蚀的一个贡献者。
