VNS‐mediated α7nAChR signaling promotes SPM synthesis via regulation of netrin‐1 expression during LPS‐induced ALI

Abstract The α7 nicotinic acetylcholine receptor (α7nAChR) plays a crucial role in the cholinergic anti‐inflammatory pathway (CAP) during sepsis‐associated acute lung injury (ALI). Increasing evidence suggests that specialized pro‐resolving mediators (SPMs) are important in resolving α7nAChR‐mediated ALI resolution. Our study aims to elucidate the pivotal role of α7nAChR in the CAP during LPS‐associated acute lung injury (ALI). By employing vagus nerve stimulation (VNS), we identified α7nAChR as the key CAP subunit in ALI mice, effectively reducing lung permeability and the release of inflammatory cytokines. We further investigated the alterations in SPMs regulated by α7nAChR, revealing a predominant synthesis of lipoxin A4 (LXA4). The significance of α7nAChR‐netrin‐1 pathway in governing SPM synthesis was confirmed through the use of netrin‐1 knockout mice and siRNA‐transfected macrophages. Additionally, our evaluation identified a synchronous alteration of LXA4 synthesis in the α7nAChR‐netrin‐1 pathway accompanied by 5‐lipoxygenase (5‐LOX), thereby confirming an ameliorative effect of LXA4 on lung injury and macrophage inflammatory response. Concurrently, inhibiting the function of LXA4 annulled the lung‐protective effect of VNS. As a result, our findings reveal a novel anti‐inflammatory pathway wherein VNS modulates netrin‐1 expression via α7nAChR, ultimately leading to LXA4 synthesis and subsequent lung protection.