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

• Published in: Advanced science Vol. 10; no. 19; pp. e2207383 - n/a
• Main Authors: Li, Juehong, Wang, Xin, Yao, Zhixiao, Yuan, Feng, Liu, Hang, Sun, Zhenyu, Yuan, Zhengqiang, Luo, Gang, Yao, Xiangyun, Cui, Haomin, Tu, Bing, Sun, Ziyang, Fan, Cunyi
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc; Wiley
• Subjects: Aging; cellular senescence; Cytokines; extracellular vesicles; Fractures; Gene expression; heterotopic ossification; Inflammation; macrophages; Proteins; pyroptosis; Senescence; Stem cells; Tissue engineering; Trauma; heterotopic ossification; pyroptosis; macrophages; cellular senescence; extracellular vesicles
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202207383

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. After soft tissue injury, macrophages infiltrate the regenerative tissues and undergo pyroptosis, followed by the elevated release of IL‐1β and high mobility group protein 1‐containing extracellular vesicles. These pyroptotic macrophage‐driven paracrine factors, through toll‐like receptor 9 (TLR9)‐involved NF‐κB signaling activation, intensify the senescent and osteogenic activity of tendon‐derived stem cells and thus encourage osteogenic healing of injured tissues, which eventually culminate in heterotopic ossification formation.