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神经生长因子激活肥大细胞会促使创伤诱导性异位骨化的形成。

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

作者信息

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

机构信息

Division of Spine Surgery, Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangdong Province, Guangzhou, China.

Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

JCI Insight. 2024 Nov 26;10(1):e179759. doi: 10.1172/jci.insight.179759.

DOI:10.1172/jci.insight.179759
PMID:39589893
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11721298/
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 LPS binding to TrkA enhanced NGF-induced TrkA phosphorylation, synergistically stimulating mast cells to release neurotrophin-3 (NT3), thereby promoting MSC 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.

摘要

软组织创伤可导致免疫系统紊乱和神经病理侵袭，由于间充质干细胞（MSC）异常软骨分化而导致异位骨化（HO）。然而，免疫和神经系统在促进HO发病机制中相互作用背后的分子机制尚不清楚。在本研究中，我们发现肥大细胞特异性缺失减轻了局部组织炎症，显著抑制了HO软骨内成骨。同样，阻断称为原肌球蛋白受体激酶A（TrkA）的神经生长因子（NGF）受体，导致组织炎症和HO出现类似减轻。此外，虽然NGF/TrkA信号传导不直接影响MSC软骨分化，但它调节创伤性软组织中的肥大细胞活化。机制上，脂多糖中的脂质A与TrkA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因子-3（NT3），从而促进原位MSC软骨分化。最后，单细胞数据集和人类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在软组织创伤中调节肥大细胞，并通过旁分泌NT3驱动HO进展。对肥大细胞的靶向早期抑制在治疗创伤性HO方面具有很大的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/e077e40984d9/jciinsight-10-179759-g246.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/bec8fd94b1a2/jciinsight-10-179759-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/316af2a76e18/jciinsight-10-179759-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/83a28c20622e/jciinsight-10-179759-g240.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/20bef8e3c9de/jciinsight-10-179759-g241.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/f4b506cbad69/jciinsight-10-179759-g242.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/e8021a265d45/jciinsight-10-179759-g243.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/43a6974090d1/jciinsight-10-179759-g244.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/2f95b828368f/jciinsight-10-179759-g245.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/e077e40984d9/jciinsight-10-179759-g246.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/bec8fd94b1a2/jciinsight-10-179759-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/316af2a76e18/jciinsight-10-179759-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/83a28c20622e/jciinsight-10-179759-g240.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/20bef8e3c9de/jciinsight-10-179759-g241.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/f4b506cbad69/jciinsight-10-179759-g242.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/e8021a265d45/jciinsight-10-179759-g243.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/43a6974090d1/jciinsight-10-179759-g244.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/2f95b828368f/jciinsight-10-179759-g245.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a29b/11721298/e077e40984d9/jciinsight-10-179759-g246.jpg

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