LAUSR

IL-17A-producing group 3 innate lymphoid cells (ILC3s) have been found to participate in the development of various phenotypes of asthma, however, little is known about how ILC3s mediate neutrophilic airway inflammation. Elevated IL-1β has been reported in neutrophilic asthma (NA) and IL-1β receptor is highly expressed on lung ILC3s. Therefore, we hypothesize that IL-1β aggravates neutrophilic airway inflammation via provoking IL-17A-producing ILC3s. We sought to determine the pathological roles of the IL-1β-ILC3-IL-17A axis in neutrophilic airway inflammation. Lung ILC subsets were measured in eosinophilic asthma (ovalbumin [OVA]/Alum) and NA (OVA/lipopolysaccharides [LPS]) murine models. Rag2-/- (lacking adaptive immunity), RORc-/- (lacking transcription factor RORγt), Rag2-/- RORc-/- (lacking adaptive immunity and ILC3s), and ILCs depletion mice were used to verify the roles of ILC3s in neutrophilic airway inflammation by measurement of CXCL-1, IL-17A, IL-22 and neutrophil counts in bronchoalveolar lavage fluid (BALF), detection of Muc5ac in lung tissues, and quantification of IL-17A-producing ILC3s after treatment of anti-IL-17A or recombinant IL-1β (rIL-1β) and its monoclonal antibody. NLRP3, Caspase 1 and their induction of IL-1β were detected in lung tissues of OVA/LPS-induced mice. The OVA/LPS model was characterized by an enrichment of airway neutrophilia, lung RORγt+ ILC3s and Th17 cytokines (IL-17A and IL-22) and neutrophilic chemokine C-X-C motif (chemokine) ligand 1 (CXCL-1), compared to the phenotypic features of airway eosinophilia, GATA3+ ILC2s and type-2 cytokines in OVA/Alum model. The concentration of CXCL-1 and neutrophil counts in BALF were decreased by anti-IL-17A. RORγt deficiency led to a decrease in IL-17A and CXCL-1 levels and neutrophil counts in BALF. ILC depletion in Rag2-/- mice ameliorated OVA/LPS-induced IL-17A, IL-22, CXCL-1 and airway neutrophil counts. IL-17A-producing ILCs and BALF neutrophil counts were significantly lower in Rag2-/- RORc-/- mice than those in Rag2-/- mice. IL-1β was highly expressed in BALF and bronchial epithelial cells (BECs) in OVA/LPS model, and administration of rIL-1β substantially aggravated airway inflammation and promoted upregulation of RORγt+ and IL-17A-producing lung ILC3s, which were reversed by anti-IL-1β. NLRP3 and Caspase 1 expressions were enhanced by OVA/LPS, and their inhibitors abolished the OVA/LPS-induced IL-1β in BECs. ILC3s play a pathogenic role in the pathogenesis of NA, which is triggered by IL-1β via promoting IL-17A production of lung ILC3s.