Interleukin 1 receptor like 1 (IL1RL1) promotes airway bacterial and viral infection and inflammation

IL1RL1, also known as ST2, is the receptor for IL-33, and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway Mycoplasma pneumoniae (Mp) and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma. However, whether ST2 contributes to Mp- and HRV-mediated airway inflammation is poorly understood. The current study sought to determine the functions of ST2 during airway Mp or HRV infection. In cultured normal human primary airway epithelial cells, ST2 overexpression (OE) increased the production of neutrophilic chemoattractant IL-8 in the absence or presence of Mp or HRV1B infection. ST2 OE also enhanced HRV1B-induced IP-10, a chemokine involved in asthma exacerbations. In the Mp-infected mouse model, ST2 deficiency vs. sufficiency significantly reduced the levels of neutrophils following the acute (≤ 24 hours) infection, while in the HRV1B-infected mouse model, ST2 deficiency significantly reduced the levels of pro-inflammatory cytokines KC, IP-10 and IL-33 in bronchoalveolar lavage (BAL) fluid. Overall, ST2 overexpression in human epithelial cells and ST2 sufficiency in mice increased the Mp and HRV load in cell supernatants and BAL fluid. After pathogen infection, ST2 deficient mice showed a higher level of host defense protein lactotransferrin in the BAL fluid. Our data suggest that ST2 promotes pro-inflammatory responses (e.g., neutrophils) to airway bacterial and viral infection, and that blocking ST2 signaling may broadly attenuate airway infection and inflammation.