Using a genetic approach employing mice with Il36r deficiency, we showed that IL-36 signaling was a critical component of the pro-inflammatory response in both CS- and CS + HN1N-exposed mice, demonstrating a role for IL-36 in both low-grade chronic lung inflammation (CS model) as well as high-grade acute microbial lung inflammation super-imposed on pre-existing chronic injury, such as during acute viral exacerbations in COPD (CS + H1N1 model). Here, IL1RL2 is linked to chronic obstructive pulmonary disease.