IL4 and IL13 cytokines exacerbate cigarette smoke-induced lung inflammation in mice by driving type 2 inflammation

Evidence of type 2 inflammation is present in 20-40% of patients with chronic obstructive pulmonary disease (COPD) and is associated with an increased risk of exacerbations. Recently, dupilumab showed efficacy in patients with COPD who had T2 inflammation. To better understand the disease biology and mechanisms of dupilumab, we aimed at developing a COPD-like mouse model with a T2 phenotype, where mice were acutely exposed to cigarette smoke and intranasally received the T2 cytokines IL4 and IL13. In this model, cigarette smoke exposure alone drove neutrophilic lung inflammation. Intranasal delivery of IL4/13 cytokines exacerbated cigarette smoke-induced lung inflammation by driving lung eosinophilia and potentiating alveolar macrophage destruction. IL4/13 also drove mucus hypersecretion and expression of both type 1 (T1) and T2 cytokines, which remained elevated in the presence of smoke. Interestingly, some T1 cytokines/chemokines were exacerbated by the combination. Finally, RNAseq analysis identified clusters on genes specifically induced by either cigarette smoke or IL4/13 exposure. This analysis also emphasized combinatorial effects of cigarette smoke and IL4/13 on gene expression, with increased expression of inflammatory genes in the context of combined cigarette smoke and T2 cytokine exposure. Overall, these findings highlight that the T2 cytokines IL4 and IL13 exacerbate cigarette smoke-induced lung inflammation in mice by driving a T2 phenotype and exacerbating overall inflammation. This suggests that IL4 and IL13 are key drivers of COPD with T2 inflammation, which is underpinned by recent clinical efficacy observed with dupilumab in this patient population.