IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Abstract

Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

“…2010; Alevy et al. 2012). Goblet cell metaplasia is increased in smokers, and several studies using cigarette smoke have shown the induction of MUC5AC (Wright et al.…”

IL13 activates autophagy to regulate secretion in airway epithelial cells

“…In this model, airway progenitor cells differentiate into functional ciliated and secretory cells when subjected to an ALI (air-liquid interface) condition for 18-21 d. The best, established model for induction of goblet cells is treatment with IL13. 11,37 We devised a protocol whereby treatment of cells with IL13 for 7 or 21 d ( Fig. 2A) resulted in an increased number of MUC5AC-positive cells and elevated levels of MUC5AC RNA (Fig.…”

“…Using approaches similar to these, our group has recently demonstrated that airway epithelial cell IL33 (interleukin 33) leads to IL13 production and lung pathology in a mouse model and in cells obtained from patients with COPD. [11][12][13][14] IL13 is a Th2-type cytokine that is elevated in COPD as well as in asthma and other lung diseases. 11,[15][16][17] In the airway, IL13 regulates the differentiation of epithelial cells to goblet cells via intracellular signaling through the IL4R (interleukin 4 receptor) and IL13RA1 (interleukin 13 receptor, a 1) receptor heterodimer and STAT6 (signal transducer and activator of transcription 6).…”

“…[11][12][13][14] IL13 is a Th2-type cytokine that is elevated in COPD as well as in asthma and other lung diseases. 11,[15][16][17] In the airway, IL13 regulates the differentiation of epithelial cells to goblet cells via intracellular signaling through the IL4R (interleukin 4 receptor) and IL13RA1 (interleukin 13 receptor, a 1) receptor heterodimer and STAT6 (signal transducer and activator of transcription 6). 12,13 Functionally, IL13 has been postulated to increase both intracellular oxidant stress and the secretion of MUC5AC (mucin 5AC, oligomeric mucus/gel forming), the dominant gel forming mucin in airway epithelial cells.…”

“…Airway epithelial cells treated with IL13 have increased oxidant activity, 18,19 higher numbers of MUC5AC-expressing cells and more MUC5AC secreted in the apical media. 11,20 The mechanism utilized by the goblet cell to adapt to the stress of IL13-mediated acceleration in activity is not known.…”