MAP2K1 dampens cigarette smoke-induced inflammation via suppression of type I interferon pathway activation.

Abstract

Chronic obstructive pulmonary disease (COPD), comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality worldwide. Mitogen-activated protein 2 kinase (MAP2K) pathway activation is present in COPD lung tissue and a genetic polymorphism in Map2k1 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of Map2k1 in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid Map2k1 (Lysm^Cre+Mek1^fl) and wild-type mice (Mek1^fl). Mice deficient in myeloid Map2k1 had enhanced CS-induced lung inflammation characterized by increased neutrophil recruitment, vascular leak, augmented expression of elastolytic matrix metalloproteinases, and increased type I interferon-stimulated gene expression. The augmented neutrophilic inflammatory response could be abrogated by IFNAR1 blockade. These findings indicate that myeloid Map2k1 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective.NEW & NOTEWORTHY Activation of the mitogen-activated protein kinases (MAPK)-ERK1/2 pathway is present in COPD lung tissue compared with healthy lungs. Our study using mice deficient in myeloid Map2k1 reveals that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation via suppression of type I interferon responses, and its expression is protective.