IL-33/sST2 balance regulates neutrophilic inflammation in the human airways

Background: Increasing number of evidences suggest that IL-33/sST2 axis associates with occurring neutrophilic inflammation but its mechanism remains unknown. Objectives: We hypothesized that IL-33/sST2 balance regulates neutrophil-related cytokine production in bronchial epithelial cells. Methods: We cultured normal human bronchial epithelial (NHBE) cells to assess functions and production mechanisms of IL-33 and sST2. We measured IL-33 and sST2 levels in exhaled breath condensate (EBC) from bronchial asthma (BA), COPD, and asthma-COPD overlap (ACO) patients (n=143) and healthy control (HC) subjects (n=11) and in sputum from BA, COPD, and ACO patients (n=31). Results: In NHBE cells, IL-33 enhanced neutrophil-related (CXCL8, CXCL1, CXCL5, and GM-CSF) and Th17-related (CCL20 and IL-6) cytokine production, which was inhibited by excess sST2. Neutrophil elastase (NE) upregulated intracellular IL-33 expression and further NE-induced cell damage caused IL-33 release into extracellular space. IL-4 and -13 enhanced sST2 production. EBC IL-33 levels were higher in ACO patients than in others (ACO vs BA plus COPD plus HC: n=15 vs 143, P=0.0008). EBC sST2 levels were higher in asthmatics than in others (BA plus ACO vs COPD plus HC: n=111 vs 47, P=0.0036). Sputum IL-33 levels correlated positively with sputum CXCL8 (r=0.56, P=0.003, n=38) and CCL20 (r=0.44, P=0.0121, n=32) levels. Sputum sST2 levels correlated positively with %FEV1 (r=0.48, P=0.0197, n=28), indicating that sST2 was protective against tissue damage. Conclusion: IL-33/sST2 axis regulates neutrophil-related cytokine production in the human airways, where high IL-33 and sST2 levels suggest presence of neutrophilic and type-2 inflammation, respectively.