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<p>Age-related inflammation plays a pivotal role in osteoarthritis (OA) pathogenesis, but the mechanism is not fully understood. Here, we identify decreased IL-36 receptor antagonists (IL-36Ra) in epidermal keratinocytes from a premature-aged skin mice model, aged mice and patients. Decreased IL-36Ra leads to increased secretion of IL-36 agonists to serum and joints, which activates proinflammatory signaling and promotes senescence in chondrocytes and synovial fibroblasts, thereby aggravates OA progression. Deletion of IL-36Ra in keratinocytes exacerbates, whereas intra-articular inhibition of IL-36R signaling effectively attenuates OA progression in male mice. Moreover, we also generate microneedles loaded with mouse recombinant IL-36Ra protein or spesolimab, insert them directly into skin to sustainably inhibit IL-36R signaling, which both clearly attenuate OA progression in male mice. Overall, our results reveal that IL-36 agonists are age-related systemic inflammatory factors released from skin to joints and contribute to OA development, and targeting IL-36R signaling in aged skin with microneedles represents a promising disease-modifying approach.</p>

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Aged skin exacerbates experimental osteoarthritis via enhanced IL-36R signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月14日

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  • Dalin Chen,
  • Chong Wang,
  • Changsheng Yang,
  • Qinwei Cheng,
  • Liangyu Chen,
  • Panpan Yang,
  • Zilin Zou,
  • Zining Wang,
  • Honghao Li,
  • Yun Xiao,
  • Junfeng Wu,
  • Ee Ke,
  • Xiaogang Wang,
  • Bin Huang,
  • Xiaochun Bai,
  • Kai Li

摘要

Age-related inflammation plays a pivotal role in osteoarthritis (OA) pathogenesis, but the mechanism is not fully understood. Here, we identify decreased IL-36 receptor antagonists (IL-36Ra) in epidermal keratinocytes from a premature-aged skin mice model, aged mice and patients. Decreased IL-36Ra leads to increased secretion of IL-36 agonists to serum and joints, which activates proinflammatory signaling and promotes senescence in chondrocytes and synovial fibroblasts, thereby aggravates OA progression. Deletion of IL-36Ra in keratinocytes exacerbates, whereas intra-articular inhibition of IL-36R signaling effectively attenuates OA progression in male mice. Moreover, we also generate microneedles loaded with mouse recombinant IL-36Ra protein or spesolimab, insert them directly into skin to sustainably inhibit IL-36R signaling, which both clearly attenuate OA progression in male mice. Overall, our results reveal that IL-36 agonists are age-related systemic inflammatory factors released from skin to joints and contribute to OA development, and targeting IL-36R signaling in aged skin with microneedles represents a promising disease-modifying approach.