Frontiers in Immunology (May 2022)
Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury
- Aritra Bhattacharyya,
- Aritra Bhattacharyya,
- Paola Torre,
- Paola Torre,
- Preeti Yadav,
- Preeti Yadav,
- Kaveh Boostanpour,
- Kaveh Boostanpour,
- Tian Y. Chen,
- Tian Y. Chen,
- Tatsuya Tsukui,
- Tatsuya Tsukui,
- Dean Sheppard,
- Dean Sheppard,
- Rieko Muramatsu,
- Robert I. Seed,
- Stephen L. Nishimura,
- James B. Jung,
- James B. Jung,
- Xin-Zi Tang,
- Xin-Zi Tang,
- Christopher D. C. Allen,
- Christopher D. C. Allen,
- Christopher D. C. Allen,
- Mallar Bhattacharya,
- Mallar Bhattacharya
Affiliations
- Aritra Bhattacharyya
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Aritra Bhattacharyya
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Paola Torre
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Paola Torre
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Preeti Yadav
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Preeti Yadav
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Kaveh Boostanpour
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Kaveh Boostanpour
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Tian Y. Chen
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Tian Y. Chen
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Tatsuya Tsukui
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Tatsuya Tsukui
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
- Dean Sheppard
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Dean Sheppard
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
- Rieko Muramatsu
- Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
- Robert I. Seed
- Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
- Stephen L. Nishimura
- Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
- James B. Jung
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- James B. Jung
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
- Xin-Zi Tang
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Xin-Zi Tang
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
- Christopher D. C. Allen
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- Christopher D. C. Allen
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
- Christopher D. C. Allen
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
- Mallar Bhattacharya
- Division of Pulmonary, Critical Care, Allergy, and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Mallar Bhattacharya
- Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA, United States
- DOI
- https://doi.org/10.3389/fimmu.2022.880887
- Journal volume & issue
-
Vol. 13
Abstract
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 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 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 P2rx4 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.
Keywords
