Title: The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice.
Authors: Lewis, Brandon W; Choudhary, Ishita; Paudel, Kshitiz; Mao, Yun; Sharma, Rahul; Wang, Yong; Deshane, Jessy S; Boucher, Richard C; Patial, Sonika; Saini, Yogesh
Published In J Immunol, (2020 09 15)
Abstract: Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. Scnn1b transgenic (Scnn1b-Tg+) mice, which recapitulate cystic fibrosis-like mucoinflammatory airway disease, deficient in innate lymphoid (Il2rg knockout mice [Il2rgKO]), adaptive immune (Rag1 knockout mice [Rag1KO]), or both systems (Il2rgKO/Rag1KO), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg+ juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of Th2-associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction. The bacterial burden was increased in Il2rgKO/Tg+ juveniles but returned to significantly lower levels in Il2rgKO/Rag1KO/Tg+ juveniles. Mechanistically, this improvement reflected reduced production of adaptive immunity-derived IL-10 and, in turn, increased activation of macrophages. Although all the mucoinflammatory features were comparable between the immunocompetent Tg+ and Rag1KO/Tg+ juveniles, the Il2rgKO/Tg+ and Il2rgKO/Rag1KO/Tg+ juveniles exhibited suppressed expression levels of Th2 markers, diminished MCM, suppressed MUC5B expression, and reduced mucus obstruction. Collectively, these data indicate that, in the context of airway mucus obstruction, the adaptive immune system suppresses antibacterial macrophage activation, whereas the innate lymphoid system contributes to MCM, mucin production, and mucus obstruction.
PubMed ID: 32817334
MeSH Terms: Animals; Cells, Cultured; Cystic Fibrosis/immunology*; Disease Models, Animal; Epithelial Cells/metabolism*; Epithelial Cells/pathology; Epithelial Sodium Channels/genetics; Homeodomain Proteins/genetics; Humans; Immunity, Innate; Inflammation/immunology*; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mucin-5B/genetics; Mucin-5B/metabolism*; Respiratory Tract Diseases/immunology*; Up-Regulation