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Sessile alveolar macrophage connexin-43 determines mechano-immunity in the lung.

ABSTRACT: Although lung immunity is pathogen induced, the immunity can also be induced by mechanical distortion of the lung. The causal basis of the lung's mechanosensitive immunity remains unclear. Here, through live optical imaging of mouse lungs, we show that alveolar stretch due to hyperinflation induced prolonged cytosolic Ca ²⁺ increases in sessile alveolar macrophages (AMs). Knockout studies revealed that the Ca ²⁺ increases resulted from Ca ²⁺ diffusion from the alveolar epithelium to sessile AMs through connexin 43 (Cx43)-containing gap junctions. Lung inflammation and injury in mice exposed to injurious mechanical ventilation were inhibited by AM-specific Cx43 knockout, or AM-specific delivery of a calcium inhibitor. We conclude, Cx43 gap junctions and calcium mobilization in sessile AMs determine the lung's mechanosensitive immunity, providing a therapeutic strategy against hyperinflation-induced lung injury.

SUBMITTER: Mthunzi L

PROVIDER: S-EPMC10245918 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.

Mthunzi Liberty L Islam Mohammad N MN Gusarova Galina A GA Bhattacharya Sunita S Karolewski Brian B Bhattacharya Jahar J

bioRxiv : the preprint server for biology 20241026

The lung's mechanosensitive immune response, which occurs when pulmonary alveoli are overstretched, is a major impediment to ventilation therapy for hypoxemic respiratory failure. The cause is not known. We tested the hypothesis that alveolar stretch causes stretch of alveolar macrophages (AMs), leading to the immune response. In lungs viewed by optical imaging, sessile AMs expressed gap junctional protein connexin-43 (Cx43), and they communicated with the alveolar epithelium through gap junctio ...[more]

PMID: 37292826

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Project description:Wanting to explore the epigenetic basis of Duchenne cardiomyopathy, we found that global histone acetylase activity was abnormally elevated and the acetylase P300/CBP-associated factor (PCAF) coimmunoprecipitated with connexin 43 (Cx43), which was N(ε)-lysine acetylated and lateralized in mdx heart. This observation was paralleled by Cx43 dissociation from N-cadherin and zonula occludens 1, whereas pp60-c-Src association was unaltered. In vivo treatment of mdx with the pan-histone acetylase inhibitor anacardic acid significantly reduced Cx43 N(ε)-lysine acetylation and restored its association to GAP junctions (GJs) at intercalated discs. Noteworthy, in normal as well as mdx mice, the class IIa histone deacetylases 4 and 5 constitutively colocalized with Cx43 either at GJs or in the lateralized compartments. The class I histone deacetylase 3 was also part of the complex. Treatment of normal controls with the histone deacetylase pan-inhibitor suberoylanilide hydroxamic acid (MC1568) or the class IIa-selective inhibitor 3-{4-[3-(3-fluorophenyl)-3-oxo-1-propen-1-yl]-1-methyl-1H-pyrrol-2-yl}-N-hydroxy-2-propenamide (MC1568) determined Cx43 hyperacetylation, dissociation from GJs, and distribution along the long axis of ventricular cardiomyocytes. Consistently, the histone acetylase activator pentadecylidenemalonate 1b (SPV106) hyperacetylated cardiac proteins, including Cx43, which assumed a lateralized position that partly reproduced the dystrophic phenotype. In the presence of suberoylanilide hydroxamic acid, cell to cell permeability was significantly diminished, which is in agreement with a Cx43 close conformation in the consequence of hyperacetylation. Additional experiments, performed with Cx43 acetylation mutants, revealed, for the acetylated form of the molecule, a significant reduction in plasma membrane localization and a tendency to nuclear accumulation. These results suggest that Cx43 N(ε)-lysine acetylation may have physiopathological consequences for cell to cell coupling and cardiac function.

Dataset Information

Sessile alveolar macrophage connexin-43 determines mechano-immunity in the lung.

Publications

Macrophage-specific lipid nanoparticle therapy blocks the lung's mechanosensitive immunity due to macrophage-epithelial interactions.

Similar Datasets

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