Mast cell activation by NGF drives the formation of trauma-induced heterotopic ossification.

IF 6.3 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-26 DOI:10.1172/jci.insight.179759

Tao Jiang, Xiang Ao, Xin Xiang, Jie Zhang, Jieyi Cai, Jiaming Fu, Wensheng Zhang, Zhenyu Zheng, Jun Chu, Minjun Huang, Zhongmin Zhang, Liang Wang

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Abstract

Soft tissue trauma can cause immune system disturbance and neuropathological invasion, resulting in heterotopic ossification (HO) due to aberrant chondrogenic differentiation of mesenchymal stem cells (MSCs). However, the molecular mechanisms behind the interaction between the immune and nervous systems in promoting HO pathogenesis are unclear. In this study, we found that mast cell-specific deletion attenuated localized tissue inflammation, with marked inhibition of HO endochondral osteogenesis. Likewise, blockage of nerve growth factor (NGF) receptor, known as tropomyosin receptor kinase A (TrkA), led to similar attenuations in tissue inflammation and HO. Moreover, while NGF-TrkA signaling did not directly affect MSCs chondrogenic differentiation, it modulated mast cell activation in traumatic soft tissue. Mechanistically, lipid A in lipopolysaccharide binding to TrkA enhanced NGF-induced TrkA phosphorylation, synergistically stimulating mast cells to release neurotrophin-3 (NT3), thereby promoting MSCs chondrogenic differentiation in situ. Finally, analysis of single-cell datasets and human pathological specimens confirmed the important role of mast cell-mediated neuroinflammation in HO pathogenesis. In conclusion, NGF regulates mast cells in soft tissue trauma, and drives HO progression via paracrine NT3. Targeted early inhibition of mast cells holds substantial promise for treating traumatic HO.

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NGF 对肥大细胞的激活推动了创伤诱导的异位骨化的形成。

软组织创伤可引起免疫系统紊乱和神经病理学侵袭，从而导致间充质干细胞（MSCs）软骨分化异常引起异位骨化（HO）。然而，免疫系统和神经系统相互作用促进HO发病机制背后的分子机制尚不清楚。在这项研究中，我们发现肥大细胞特异性缺失可减轻局部组织炎症，并明显抑制HO内软骨成骨。同样，阻断神经生长因子（NGF）受体（即肌钙蛋白受体激酶A（TrkA））也会导致类似的组织炎症和HO衰减。此外，虽然NGF-TrkA信号传导并不直接影响间充质干细胞的软骨分化，但它能调节创伤软组织中肥大细胞的活化。从机理上讲，脂多糖中的脂质A与TrkA的结合增强了NGF诱导的TrkA磷酸化，协同刺激肥大细胞释放神经营养素-3（NT3），从而促进间充质干细胞的原位软骨分化。最后，单细胞数据集和人体病理标本分析证实了肥大细胞介导的神经炎症在 HO 发病机制中的重要作用。总之，NGF能调节软组织创伤中的肥大细胞，并通过旁分泌NT3驱动HO进展。早期靶向抑制肥大细胞为治疗创伤性 HO 带来了巨大希望。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JCI insight Medicine-General Medicine

CiteScore

13.70

自引率

1.20%

发文量

543

审稿时长

6 weeks

期刊介绍： JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.