Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection.

Zhao-Wei Gao, Ling Li, Yuan-Yuan Huang, Cai-Qi Zhao, Shuang-Jia Xue, Jie Chen, Zhong-Zhou Yang, Jin-Fu Xu, Xiao Su

Acta pharmacologica Sinica 2021 Oct

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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 Foxo1a reduced α7nAChR activation and IL-4 induced Arg1 expression in PR8-infected BMDM. Therefore, vagal-α7nAChR signaling is a novel therapeutic target for treating lung inflammatory responses during an influenza infection. © 2020. The Author(s).

Citation

Zhao-Wei Gao, Ling Li, Yuan-Yuan Huang, Cai-Qi Zhao, Shuang-Jia Xue, Jie Chen, Zhong-Zhou Yang, Jin-Fu Xu, Xiao Su. Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection. Acta pharmacologica Sinica. 2021 Oct;42(10):1642-1652