Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury

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 m...

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Vydáno v:	Frontiers in Immunology Ročník 13; s. 880887
Hlavní autoři:	Bhattacharyya, Aritra, Torre, Paola, Yadav, Preeti, Boostanpour, Kaveh, Chen, Tian Y., Tsukui, Tatsuya, Sheppard, Dean, Muramatsu, Rieko, Seed, Robert I., Nishimura, Stephen L., Jung, James B., Tang, Xin-Zi, Allen, Christopher D. C., Bhattacharya, Mallar
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Switzerland Frontiers Media SA 12.05.2022 Frontiers Media S.A
Témata:	2.1 Biological and endogenous factors Adenosine Triphosphate Adenosine Triphosphate - metabolism Aetiology Animals Bleomycin Bleomycin - pharmacology Calcium Calcium - metabolism calcium imaging Connexin 43 Connexin 43 - genetics Connexin 43 - metabolism fibroblast Fibroblasts Fibroblasts - metabolism Idiopathic Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis - metabolism Immunologic diseases. Allergy Immunology Knockout Lung lung fibrosis macrophage Macrophages Macrophages - metabolism Medical Microbiology Mice Mice, Knockout P2RX4 RC581-607 Respiratory macrophage P2RX4 fibroblast calcium imaging lung fibrosis
ISSN:	1664-3224, 1664-3224
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Shrnutí:	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 ΔCx43 ) 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 ΔCx43 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors have contributed equally to this work This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology Edited by: Zhilong Jiang, Fudan University, China Reviewed by: Dominik Rückerl, The University of Manchester, United Kingdom; Jonathan Soboloff, Temple University, United States
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2022.880887