Abstract
Pseudomonas aeruginosa (PA) infection increases reactive oxygen species (ROS), and earlier, we have shown a role for NADPH oxidase-derived ROS in PA-mediated lung inflammation and injury. Here, we show a role for the lung epithelial cell (LEpC) NOX4 in PA-mediated chromatin remodeling and lung inflammation. Intratracheal administration of PA to Nox4flox/flox mice for 24 h caused lung inflammatory injury; however, epithelial cell-deleted Nox4 mice exhibited reduced lung inflammatory injury, oxidative stress, secretion of pro-inflammatory cytokines, and decreased histone acetylation. In LEpCs, NOX4 was localized both in the cytoplasmic and nuclear fractions, and PA stimulation increased the nuclear NOX4 expression and ROS production. Downregulation or inhibition of NOX4 and PKC δ attenuated the PA-induced nuclear ROS. PA-induced histone acetylation was attenuated by Nox4-specific siRNA, unlike Nox2. PA stimulation increased HDAC1/2 oxidation and reduced HDAC1/2 activity. The PA-induced oxidation of HDAC2 was attenuated by N-acetyl-L-cysteine and siRNA specific for Pkc δ, Sphk2, and Nox4. PA stimulated RAC1 activation in the nucleus and enhanced the association between HDAC2 and RAC1, p-PKC δ, and NOX4 in LEpCs. Our results revealed a critical role for the alveolar epithelial NOX4 in mediating PA-induced lung inflammatory injury via nuclear ROS generation, HDAC1/2 oxidation, and chromatin remodeling.
Highlights
Pseudomonas aeruginosa is a common opportunistic Gram-negative bacterium that causes serious life-threatening and nosocomial infection, including pneumonia
We previously reported that the upregulation of Nox4 in mouse lung infected with P
P. aeruginosa challenge for 24 h stimulated NAPH Oxidase 4 (NOX4) expression in lung tissue lysates from Nox4flox/flox but not in LEp-Nox4 knock out (KO) mice. These results show that deletion of Nox4 in the alveolar epithelial cells protected mice from P. aeruginosamediated inflammatory injury by attenuating infiltration of polymorphonuclear leukocytes (PMNs) into the lung and reducing levels of reactive oxygen species (ROS) and pro-inflammatory cytokines in the tissue lysates from tamoxifen-treated control and LEp-Nox4 KO mice treated with P
Summary
Pseudomonas aeruginosa is a common opportunistic Gram-negative bacterium that causes serious life-threatening and nosocomial infection, including pneumonia. P. aeruginosa infection of the lung alters the host genome to facilitate its Antioxidants 2021, 10, 477. Antioxidants 2021, 10, 477 replication and virulence and initiates cascade of events in the host, including innate immune responses, reactive oxygen species (ROS) generation, cytokine production, inflammation, dysregulated lipid metabolism, and modulation of epigenetic factors [8,9,10,11]. Recent studies strongly suggest the regulation of sphingolipid metabolism and signaling pathways by P. aeruginosa infection of the mouse lung. P. aeruginosa infection of the mouse lungs and epithelial cells modulated histone H3 and H4 acetylation via protein kinase C (PKC) δ-dependent nuclear SPHK2 phosphorylation and S1P production [14]
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