焦亡巨噬细胞和衰老细胞之间依赖NLRP3的串扰协调异常伤口愈合过程中创伤诱导的异位骨化,Advanced Science

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焦亡巨噬细胞和衰老细胞之间依赖NLRP3的串扰协调异常伤口愈合过程中创伤诱导的异位骨化
Advanced Science ( IF 14.3 ) Pub Date : 2023-05-19 , DOI: 10.1002/advs.202207383
Juehong Li _{1,

2,

3} , Xin Wang _{1,

2,

3} , Zhixiao Yao _{1,

2,

3} , Feng Yuan ₁ , Hang Liu _{1,

2,

3} , Zhenyu Sun _{1,

2,

3} , Zhengqiang Yuan _{1,

2,

3} , Gang Luo _{1,

2,

3} , Xiangyun Yao _{1,

2,

3} , Haomin Cui _{1,

2,

3} , Bing Tu _{1,

2,

3} , Ziyang Sun _{1,

2,

3} , Cunyi Fan _{1,

2,

3}

Affiliation

异位骨化（HO）代表对软组织损伤的不必要的骨化伤口愈合反应，导致灾难性的肢体功能障碍。最近的研究证实炎症和细胞衰老参与组织愈合过程，但它们在 H2O 中的作用仍有待阐明。在这里，焦亡巨噬细胞引起肌腱衍生干细胞（TDSC）衰老的新串扰被揭示，以促进创伤诱导的 HO 形成过程中的成骨愈合。巨噬细胞焦亡阻断可减少 NLRP3 敲除小鼠的衰老细胞负担和 H2O 形成。焦亡驱动的 IL-1 β巨噬细胞分泌的细胞外囊泡 (EV) 被确定可促进 TDSC 衰老和由此产生的成骨作用。从机制上讲，巨噬细胞焦亡会增强高迁移率族蛋白 1 (HMGB1) 的外泌体释放，该蛋白直接结合 TDSC 中的 TLR9 以触发病态信号传导。NF- κ B 信号传导被证实是 TDSC 响应含有 HMGB1 的 EV 和 IL-1 β的汇聚下游途径。这项研究增加了对基于异常再生的 H2O 形成理论的见解，并促进了治疗策略的开发。

"点击查看英文标题和摘要"

NLRP3-Dependent Crosstalk between Pyroptotic Macrophage and Senescent Cell Orchestrates Trauma-Induced Heterotopic Ossification During Aberrant Wound Healing

Heterotopic ossification (HO) represents an unwanted ossific wound healing response to the soft tissue injury which caused catastrophic limb dysfunction. Recent studies established the involvement of inflammation and cellular senescence in the tissue healing process, though their role in HO still remained to be clarified. Here, a novel crosstalk where the pyroptotic macrophages aroused tendon-derived stem cells (TDSCs) senescence is revealed to encourage osteogenic healing during trauma-induced HO formation. Macrophage pyroptosis blockade reduces the senescent cell burden and HO formation in NLRP3 knockout mice. Pyroptosis-driven IL-1β and extracellular vesicles (EVs) secretion from macrophages are determined to motivate TDSCs senescence and resultant osteogenesis. Mechanistically, pyroptosis in macrophages enhances the exosomal release of high mobility group protein 1 (HMGB1), which directly bounds TLR9 in TDSCs to trigger morbid signaling. NF-κB signaling is confirmed to be the converging downstream pathway of TDSCs in response to HMGB1-containing EVs and IL-1β. This study adds insights into aberrant regeneration-based theory for HO formation and boosts therapeutic strategy development.

更新日期：2023-05-19

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