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

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 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid () and wild-type mice (). Mice deficient in myeloid 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 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective. 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 reveals that 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.