Vagal circuit-α7 nicotinic acetylcholine receptor (α7nAChR,coded by Chrna7) signaling can modulate lung proinflammatory responses.Arginase 1 (ARG1) plays a crucial role in the resolution of lung inflammation.However,whether vagal-α7nAChR signaling can regulate lung inflammation and ARG1 expression during an influenza infection is elusive.Here,we found that lung and spleen IL-4+ cells and lung ARG1 expression were reduced;however,bronchoalveolar lavage (BAL) protein and leukocytes and lung inflammatory cytokines were increased in PR8 (A/Puerto Rico/8/1934,H1N1)-infected vagotomized mice when compared to the control.In PR8-infected α7nAChR-deficient mice,lung Arg1,Il10,and Socs3 expression and BAL Ly6C+CD206+ cells were reduced.PR8-infected Chrna7+/+ recipient mice reconstituted with Chrna7-/-bone marrow had a lower survival as compared to PR8-infected Chrna7+/+ recipient mice reconstituted with Chrna7+/+ bone marrow.Mechanistically,the activation of α7nAChR by its agonist GTS-21 could enhance IL-4-induced Arg1 expression,reduced Nos2,and TNF-α expression in PR8-infected bone marrow-derived macrophages (BMDM).Stimulation with IL-4 increased phosphorylation of STAT6 and activation of α7nAChR increased STAT6 binding with the ARG1 promoter and relieved IL-4-induced H3K27me3 methylation by increasing JMJD3 expression in PR8-infected BMDM.Inhibition of JMJD3 increased H3K27me3 methylation and abolished α7nAChR activation and IL-4 induced ARG1 expression.Activation of α7nAChR also reduced phosphorylation of AKT1 and contained FOXO1 in the nucleus.Knockdown of Foxo1α reduced α7nAChR activation and IL-4 induced Arg1 expression in PR9-infected BMDM.Therefore,vagal-α7nAChR signaling is a novel therapeutic target for treating lung inflammatory responses during an influenza infection.