Signals of vagal circuits engaging with AKT1 in α7 nAChR(+)CD11b(+) cells lessen E. coli and LPS-induced acute inflammatory injury.

Vagal circuits-α7 nAChR (α7 nicotinic acetylcholine receptor, coded by Chrna7) signaling utilizes spleen as a hub to dampen systemic inflammatory responses. Vagal innervations also extend to the distal airways and alveoli. Vagotomy and deficiency of α7 nAChR deteriorate E. coli and lipopolysaccharide (LPS)-induced acute lung inflammatory responses; however, the underlying mechanisms remain elusive. Here, we hypothesized that vagal circuits would limit splenic release and lung recruitment of α7 nAChR(+)CD11b(+) cells (CD11b is coded by Itgam, a surface marker of monocytes and neutrophils) via phosphorylation of AKT1 and that this process would define the severity of lung injury. Using both E. coli and LPS-induced lung injury mouse models, we found that vagotomy augmented splenic egress and lung recruitment of α7 nAChR(+)CD11b(+) cells, and consequently worsened lung inflammatory responses. Rescue of vagotomy with an α7 nAChR agonist preserved α7 nAChR(+)CD11b(+) cells in the spleen, suppressed recruitment of these cells to the lung and attenuated lung inflammatory responses. Vagal signals via α7 nAChR promoted serine473 phosphorylation of AKT1 in α7 nAChR(+)CD11b(+) cells and stabilized these cells in the spleen. Deletion of Akt1 enhanced splenic egress and lung recruitment of α7 nAChR(+)CD11b(+) cells, which elicited neutrophil-infiltrated lung inflammation and injury. Vagotomy and double deletion of Chrna7 and Itgam reduced serine473 phosphorylation of AKT1 in the spleen and BAL (bronchoalveolar lavage) Ly6C(int)Gr1(hi) neutrophils and Ly6C(hi) monocytes, and they facilitated the recruitment of neutrophils and monocytes to the airspaces of E. coli-injured lungs. Double deletion of Chrna7 and Itgam increased lung recruitment of monocytes and/or neutrophils and deteriorated E. coli and LPS-induced lung injury. Thus, signals of vagal circuits engaging with AKT1 in α7 nAChR(+)CD11b(+) cells attenuate E. coli and LPS-induced acute lung inflammatory responses. Targeting this signaling pathway could provide novel therapeutic strategies for treating acute lung injury.