Mouse model of late-onset neutrophilic asthma reveals an epithelium-lymphocyte-neutrophil communication circuit underlying destructive airway neutrophilia.

Abstract While childhood-onset asthma is extensively modeled in labs and includes TH2 cell driven-, steroid-responsive, eosinophilic etiology, little is understood about late-onset asthma which presents as severe, steroid-resistant, and destructive neutrophilic disease with poor outcomes. Lack of appropriate disease models widens this knowledge gap leading to fewer therapies and poorer quality of life for neutrophilic asthma patients. Here, we discover that while conventional models of allergic asthma (relying on naïve sensitized mice acutely challenged with aerosolized ovalbumin) induces eosinophilic asthma, transient and recurrent aeroallergenic exposure over extended durations (as would occur in humans progressing into adulthood) reprograms the lung myeloid and lymphoid landscape to instigate neutrophilic asthma. Mice with such lung history harbor diverse clusters of lung-resident CD4+ TRM cells including a novel RORγt-negative-IL17A+ TH17 subset; the latter detectable in asthmatic adult human lungs. On allergen reencounter, these RORγt-negative TH17 cells, rapidly secrete IL-17A which signals into lung epithelial and stromal cells to express CXCL5 and induce neutrophilic asthma including peribronchial neutrophilia, vascular leakage and lung damage. We find that lung epithelial antigen presentation is crucial to regulate disease severity by skewing CD4+ TRM phenotypes in asthmatic lungs. Specifically, epithelial MHC-II supports TH1 TRM cells and IFNγ secretion; the latter being a potent suppressor of IL-17A-induced CXCL5 and airway neutrophilia. Thus, using a relevant model of the disease, we identify an ‘epithelium-lymphocyte-neutrophil’ circuitry as a critical regulator of late-onset neutrophilic asthma. Supported by NIH grants including HL147461 to F.T.K., HL142199 to K.A.B., HL136725 to M.R.J., GM120060 and HL111449 to L.J.Q., AI115053, HL135756, and HL137081 to J.P.M. and T32 HL007035 for support of trainees.