Austin, S. R. | bioRxiv Science

bioRxiv2024

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 that resembles asthma. We show that Mapk13 gene-knockout mice handle acute infectious illness as expected but are protected against basal-epithelial stem cell (basal-ESC) hyperplasia and mucous metaplasia. In corresponding organoid models, Mapk13-deficiency directly controls the basal-ESC program for stemness endpoints of hyperplasia and mucous metaplasia. Extension to human studies shows induction/activation of MAPK13 in basal-epithelial cells in lung tissue samples from asthma and COPD patients. Further, in human organoid models, MAPK13 mRNA knockdown regulates basal-ESC stemness similarly to mouse models. Together, the data identify MAPK13 as a control point for structural remodeling after epithelial injury and a suitable target for down-regulation as a disease-modifying strategy.

immunology↗

bioRxiv2023

A new MAPK13-guided inhibitor for respiratory inflammation and mucus production

Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of MAPK13 versus MAPK14 gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively down-regulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease. New and noteworthyThis study describes the discovery of a potent MAPK13-14 inhibitor and its effectiveness in models of respiratory airway disease. The findings thereby provide a scheme for pathogenesis and therapy of lung diseases (e.g., asthma, COPD, Covid-19, post-viral and allergic respiratory disease) and related conditions that implicate MAPK13-14 function. The findings also refine a hypothesis for epithelial and immune cell functions in respiratory disease that features MAPK13 as a possible component of this disease process.

immunology↗