The P2X7R/NLRP3 inflammasome axis suppresses enthesis regeneration through inflammatory and metabolic macrophage-stem cell cross-talk

  • Sci Adv. 2025 Apr 25;11(17):eadr4894. doi: 10.1126/sciadv.adr4894.
Haihan Gao  1  2 ,  Liren Wang  1  2 ,  Yangbao Lyu  1 ,  Haocheng Jin  1 ,  Zhiqi Lin  1 ,  Yuhao Kang  1 ,  Ziyun Li  1 ,  Xueying Zhang  1 ,  Yuhan Jiang  1 ,  Guoyang Zhang  1 ,  Zaijin Tao  1 ,  Xiaofeng Zhang  3 ,  Bin Yang  4 ,  Xingyu Bai  4 ,  Xin Ma  1 ,  Shen Liu  1 ,  Jia Jiang  1
Affiliations
  • 1. Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
  • 2. Regenerative Sports Medicine and Translational Youth Science and Technology Innovation Workroom, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
  • 3. Department of Orthopedic Surgery, Jinshan Branch of Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201500, China.
  • 4. National Key Laboratory of Advanced Micro and Nano Manufacture Technology, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 40279432 DOI: 10.1126/sciadv.adr4894
Abstract

The regeneration of the enthesis remains a formidable challenge in regenerative medicine. However, key regulators underlying unsatisfactory regeneration remain poorly understood. This study reveals that the purinergic receptor P2X7 (P2X7R)/NOD-like Receptor family protein 3 (NLRP3) inflammasome axis suppresses enthesis regeneration by amplifying IL-1β-mediated inflammatory cross-talk and suppressing docosatrienoic acid (DTA) metabolic cross-talk. NLRP3 inflammasomes were activated in macrophages following enthesis injury, thereby impairing the histological and functional recovery of the injured enthesis. Single-cell RNA Sequencing (scRNA-seq) indicated that NLRP3 knockout attenuated pathological inflammation and ameliorated the detrimental effects of IL-1β signaling cross-talk. Furthermore, NLRP3 inflammasomes suppressed the secretion of anti-inflammatory cytokines (IL-10 and IL-13) and DTA. The NLRP3 inflammasome-mediated secretome reduced differentiation and migration of stem cells. Neutralizing IL-1β or replenishing docosatrienoic acid accelerated enthesis regeneration. Moreover, conditional knockout of P2rx7 in myeloid cells attenuated NLRP3 inflammasome activation and facilitated enthesis regeneration. This study demonstrates that the P2X7R/NLRP3 inflammasome axis represents a promising therapeutic target for enthesis repair.

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