Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States.
Front Immunol. 2022 May 12;13:880887. doi: 10.3389/fimmu.2022.880887. eCollection 2022.
Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (Mac) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, Mac mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.
巨噬细胞是旁分泌信号分子，通过与实质细胞的相互作用调节组织对损伤的反应。最近已经表明，缝隙连接半通道介导巨噬细胞中 ATP 的外排，导致相邻细胞中的细胞质钙离子反应。在这里，我们报告说，与野生型巨噬细胞相比，缺失连接蛋白 43 的肺巨噬细胞（Mac）向细胞外空间的 ATP 外排减少，并且在共培养的成纤维细胞中诱导的细胞质钙离子反应减少。此外，Mac 小鼠在博莱霉素诱导的损伤后肺纤维化减少。对人类和小鼠的单细胞数据进行分析，我们发现 P2rx4 是肺成纤维细胞中表达最高的 ATP 受体和钙离子通道，并且在纤维化的情况下其表达增加。在博莱霉素模型中，成纤维细胞特异性缺失 P2rx4 可减少肺纤维化和肺成纤维细胞中胶原蛋白的表达。总之，这些研究揭示了肺巨噬细胞中 Cx43 依赖性促纤维化作用，并支持将成纤维细胞 P2rx4 作为肺纤维化治疗靶点的发展。
