P2X7R/NLRP3炎性小体轴通过炎性和代谢性巨噬细胞-干细胞串扰抑制内端再生

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-04-25 DOI:10.1126/sciadv.adr4894

Haihan Gao, Liren Wang, Yangbao Lyu, Haocheng Jin, Zhiqi Lin, Yuhao Kang, Ziyun Li, Xueying Zhang, Yuhan Jiang, Guoyang Zhang, Zaijin Tao, Xiaofeng Zhang, Bin Yang, Xingyu Bai, Xin Ma, Shen Liu, Jia Jiang

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引用次数: 0

摘要

椎体的再生仍然是再生医学的一个巨大挑战。然而，令人不满意的再生背后的关键调控因素仍然知之甚少。本研究揭示嘌呤能受体P2X7 (P2X7R)/ nod样受体家族蛋白3 （NLRP3）炎性小体轴通过放大il -1β介导的炎症串扰和抑制二十碳三烯酸（DTA）代谢串扰来抑制端胞体再生。内皮损伤后，巨噬细胞中NLRP3炎性小体被激活，从而损害内皮损伤的组织学和功能恢复。单细胞RNA测序（scRNA-seq）显示，Nlrp3敲除可减轻病理性炎症，并改善IL-1β信号串扰的有害影响。此外，NLRP3炎性小体抑制抗炎细胞因子（IL-10和IL-13）和DTA的分泌。NLRP3炎症小体介导的分泌组减少干细胞的分化和迁移。中和IL-1β或补充二十二碳三烯酸可加速内端再生。此外，髓细胞中P2rx7的条件敲除可减弱NLRP3炎性体的激活并促进终端再生。本研究表明，P2X7R/NLRP3炎症小体轴是内皮修复的一个有希望的治疗靶点。

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

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

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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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.