Ncf1 Governs Immune Niches in the Lung to Mediate Pulmonary Inflammation in Mice

• Neutrophil cytosolic factor 1 (Ncf1) is a major genetic factor associated with autoimmune diseases and has been identified as a key player in autoimmune mediated inflammation. We addressed the role ofNcf1in an antigen-induced pulmonary inflammation model, and found that theNcf1m1jmutation, causing a deficient reactive oxygen species response, alleviated disease. TheNcf1m1jmutation was associated with a reduced inflammatory cell infiltration in airways, but had limited effect on mucus secretion, antibody production and lung fibrosis. The disease remission in theNcf1mutated mice was reversed when functionalNcf1was transgenically expressed in alveolar macrophages, suggesting that the cellular inflammation was depended on functionalNcf1in alveolar macrophages. By determining cytokine and chemokine profiles in lung and serum, we found thatNcf1deficiency allowed an increased expression of Th1 cytokines, including TNF-α, IFN-γ and IL-12. Since also epithelial cytokines were found to be regulated byNcf1, we tested the effect ofNcf1in IL-33 and IL-25 induced lung inflammation models. Mice with theNcf1m1jmutation showed less sensitivity to IL-33, but not IL-25, induced lung inflammation, in a macrophage independent manner. The mice with deficientNcf1showed a reduced eosinophil infiltration and group 2 innate lymphoid cell (ILC2) activation. The production of IFN-γ in CD4+T cells was increased, whereas IL-5 and IL-13 in ILC2 were decreased. Importantly, anti-IFN-γ antibody treatment ofNcf1deficient mice increased eosinophil infiltration and rescued ILC2 activation in the lung. We conclude thatNcf1deficiency enhances Th1 response, deactivates ILC2, and protects against pulmonitis.

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