MAPK13 controls structural remodeling and disease after epithelial injury

All living organisms are charged with repair after injury particularly at epithelial barrier sites, but in some cases this response leads instead to structural remodeling and long-term disease. Identifying the molecular and cellular control of this divergence is key to disease modification. In that regard, stress kinase control of epithelial stem cells is a rational entry point for study. Here we examine the potential for mitogen-activated protein kinase 13 (MAPK13) regulation of epithelial stem cells using models of respiratory viral injury and post-viral lung disease. We show that Mapk13 gene-knockout mice handle acute infectious illness as expected but are protected against structural remodeling manifest as basal-epithelial stem cell (basal-ESC) hyperplasia-metaplasia, immune activation, and mucinous differentiation. In corresponding cell models, Mapk13-deficiency directly attenuates basal-ESC growth and organoid formation. Extension to human studies shows marked induction/activation of basal-cell MAPK13 in clinical samples of comparable remodeling found in asthma and COPD. Here again, MAPK13 gene-knockdown inhibits human basal-ESC growth in culture. Together, the data identify MAPK13 as a control for structural remodeling and disease after epithelial injury and as a suitable target for down-regulation as a disease-modifying strategy. New and noteworthyThis study identifies a distinct role for stress kinase MAPK13 in controlling the epithelial stem cell response to injury and the consequent development of tissue remodeling. The present model has direct implications for lung injury and subsequent disease triggered by respiratory viruses and other inhaled toxins, but the tissue distribution of MAPK13 implies related actions at other barrier sites. The findings also refine a hypothesis for therapeutic intervention based on proper scaling of MAPK13 function including down-regulation with selective kinase inhibitors.