IL-17A+group 2 innate lymphoid cells elicit mixed airway inflammation in chronic obstructive pulmonary disease

Abstract

ABSTRACTRationaleGroup 2 innate lymphoid cells (ILC2s) are important in asthma pathogenesis but their role in chronic obstructive pulmonary disease (COPD) has been controversial. COPD is associated with impaired function and expression of surfactant protein D (SP-D), a protective immune regulator in the lung.ObjectivesWe aimed to establish the pathogenic significance of ILC2s and their regulation by SP-D in COPD.MethodsLung function, sputum and peripheral blood SP-D, immune cell and cytokine profile were evaluated in COPD and healthy subjects. Responsiveness to the air pollutant ozone (O3) was studied in COPD-like SP-D-/-and conditional SP-D expressor mouse models. The effects of recombinant SP-D on isolated ILC2 gene and protein expression were investigatedin vitro.Measurements and Main ResultsCOPD patients with elevated sputum GATA3+ILC2s (the ILC2highgroup) showed significantly increased numbers of eosinophils, neutrophils and IL-17+ILC2s. The ILC2 counts in ILC2high(but not ILC2low) sputum samples correlated with lung function, airway inflammation and leakage of degraded SP-D into the circulation. SP-D deficiency in O3-exposed mice enhanced airway neutrophilia, promoted activation and RORγt and IL-17 expression by ILC2s in the lung. Recombinant SP-D suppressed both IL-13 and IL-17A in ILC2sin vitro. Adoptively transferred ILC2 induced neutrophilia in O3-exposed Rag2/γc-/-mice in an IL-17A dependent manner.ConclusionsIL-17A+ILC2s were associated with a mixed neutrophilic and eosinophilic inflammation in COPD sputum and drove O3-induced exacerbation of airway inflammation in a mouse model. SP-D directly inhibited IL-17A+ILC2s. Presence of IL-17A+ILC2s may predict COPD severity.