Ablation of adaptive immune responses facilitates increased bacterial clearance in murine model of defective mucociliary clearance

Abstract

Abstract Defective mucociliary clearance (MCC) associated with muco-obstructive lung diseases may compromise effective clearance of aspirated bacteria. Mucus hypersecretion is often associated with mucous cell metaplasia (MCM) of airway epithelium, which is a Type 2 immune response. Whether ablation of Type 2 response abolishes MCM/muco-obstruction, and thus, enhances bacterial clearance remains untested. Accordingly, we hypothesized that the ablation of adaptive immune responses will promote bacterial clearance in murine model of defective MCC, i.e., Scnn1b [Sodium channel, non-voltage-gated 1, beta] transgenic (Tg+) mice. The Tg+ model recapitulates hallmarks of muco-obstructive airways, including MCM and bacterial infections. The Type 2 response deficient (Il2rg−/−, Rag1−/− and Il2rg −/−\Rag1−/−) mice strains on Tg+ background were observed at neonatal age (6–7 days) for bacterial clearance response. Our data suggest that while Il2rg−/− mice [lacking innate lymphoid cells (ILC)] had significantly impaired bacterial clearance in control (Tg−) as well as Tg+, the Rag1−/−mice [lacking adaptive immune response] did not exhibit impaired bacterial clearance in Tg− as well as Tg+ neonates. The defective bacterial clearance in Il2rg−/− was not due to reduced phagocyte recruitment. Interestingly, Il2rg −/−\Rag1−/− mice had significantly improved bacterial clearance, an observation that remains a focus of our ongoing investigation. Our analyses revealed absence of IL-10 in Rag1−/−mice was associated with morphological activation of macrophages. Taken together, our current data suggest that while ILCs are essential for bacterial clearance, the adaptive immune responses suppress macrophage’s antibacterial function.