Evidence for Interleukin-17C governing interleukin-17A pathogenicity and promoting asthma endotype switching in bronchiectasis.

Abstract

The management of bronchiectasis-asthma overlap (BAO) is an important clinical issue to be addressed. Little is known regarding the endotype of BAO. Here we recruit patients with a primary diagnosis of bronchiectasis and co-existing asthma. The levels of interleukin (IL)-17C are positively correlated with the levels of IL-17A or group 3 innate lymphoid cells (ILC3s) in peripheral blood samples from patients with BAO. An in vivo mouse model of Pseudomonas aeruginosa chronic lower respiratory tract infection followed by ovalbumin-induced asthma shows that IL-17C potentiates IL-17A expression via interacting with IL-17 receptor E in ILC3s. Additionally, ablation of Il17re in mice attenuates ILC3 responses and IL-17A-mediated asthma endotype switching towards neutrophilic asthma driven by P. aeruginosa chronic lower respiratory tract infection. Lastly, impaired epithelial barrier integrity by P. aeruginosa exposure is associated with IL-17C production in vitro. Collectively, our study implicates evidence for IL-17C governing IL-17A pathogenicity and promoting asthma endotype switching in bronchiectasis, implicating IL-17C as a potential therapeutic target for individuals with BAO.