IL-4R signaling in B cells mediates control of IL-17A dependent emphysema triggered by N. brasiliensis infection

Abstract The intestinal nematode parasite, Nippostrongylus brasiliensis (Nb), transiently resides in the lung and causes lung damage, which is then rapidly repaired. However, the repaired lung eventually develops emphysema and the mechanisms contributing to this chronic lung pathology remain poorly defined. Here we show that emphysema, as measured by mean linear intercept measurements (Lm) of alveolar spaces, develops as early as 7 days after Nb inoculation and is associated with increased gene expression of Il17A, neutrophil elastase (ELA), and macrophage matrix metalloproteinase 12 (Mmp12) in the lung. Transfer of Nb-primed neutrophils or macrophages to naïve recipients results in emphysema, and these cells expressed high level of ELA and Mmp12, respectively. Neutralization of IL-17A using anti-IL-17A antibody curbed development of emphysema, and decreased influx of neutrophils in the lung and gene expression of Il17A. Parasite infection in B cell deficient Jh−/− mice results in a more severe emphysema when compared to wild-type mice or FcRγ−/− mice, and is associated with higher numbers of neutrophils and macrophages, as well as increased expression of Il17a, ELA2 and Mmp12 in the lung. Transfer of B lymphocytes from wild-type mice or IL-10−/− mice, but not from IL4Rα−/− mice, to recipient Jh−/− mice can restore control of emphysema and downregulate IL-17A. B cells from lung tissue of Nb-primed wild type but not IL4Rα−/− mice expressed high level of Relmα. Taken together, these data suggest that IL-17A triggers infiltration of neutrophils and macrophages that contribute to chronic emphysema, which is controlled by IL-4R dependent B regulatory cells expressing high levels of Relmα.