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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Published in:Frontiers in Immunology Vol. 13; p. 880887
Main Authors: 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
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media SA 12.05.2022
Frontiers Media S.A
Subjects:
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
Online Access:Get full text
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Summary: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.
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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