Cigarette smoke induces PPP1R15A via oxidative stress to modulate inflammatory cytokine production by bronchial epithelial cells

Abstract

Cigarette smoke is the principal cause of chronic obstructive pulmonary disease (COPD) in Western societies. It induces pulmonary inflammation and activates multiple stress signalling pathways in bronchial epithelial cells, including the integrated stress response (ISR). The ISR is triggered by phosphorylation of the translation initiation factor eIF2 in response to a variety of insults and is functionally antagonised by the eIF2 phosphatase subunit PPP1R15A. Deletion of PPP1R15A exaggerates the ISR and, in many models, protects against cellular stress. However, loss of PPP1R15A was also shown to exaggerate pulmonary fibrosis in bleomycin-challenged mice. We therefore wished to understand the role of PPP1R15A in the pulmonary response to cigarette smoke, which can cause both COPD and pulmonary fibrosis. Whole cigarette smoke rapidly activated the ISR in differentiated mucociliary human primary bronchial epithelial cells, with those from COPD patients exhibiting higher levels of ISR. Acute exposure to cigarette smoke condensate induced a pro-inflammatory cytokine response accompanied by PPP1R15A expression. In this model, PPP1R15A induction was independent of eIF2 phosphorylation but was suppressed by antioxidants, suggesting a response to oxidative stress. In vivo studies in mice revealed that PPP1R15A deficiency enhanced the secretion of proinflammatory cytokines in mice, suggesting a regulatory role for PPP1R15A in modulating the inflammatory response to smoke. Taken together, these data suggest that PPP1R15A is induced by cigarette smoke by an ISR-independent oxidative stress mechanism and ameliorates the pro-inflammatory cytokine response to cigarette smoke