Sympathetic signaling activation alleviated acute respiratory distress syndrome via the HDC/SLC7A11 axis in lipopolysaccharide-induced macrophages.

Acute respiratory distress syndrome (ARDS) represents a severe pulmonary condition characterized by excessive inflammation, wherein alveolar macrophages (AMs), pivotal components of the innate immune system, play a critical role in the pathogenesis of the disease. Despite its high morbidity and mortality, effective targeted therapies for ARDS remain unavailable. Norepinephrine (NE) is an endogenous neurotransmitter with immunomodulatory and anti-inflammatory properties, and has been reported to mitigate ARDS symptoms in sepsis models. While sympathetic signaling exerts protective effects, the underlying immunomodulatory mechanisms-especially those involving macrophages-remain poorly defined. Our in vitro experiments demonstrated that NE confers protection against LPS-induced injury in AMs by limiting lipid peroxidation, sustaining mitochondrial integrity, and upregulating antioxidant regulators SLC7A11 and GPX4, leading to improved cell viability. Mechanistically, the anti-ferroptotic effect of NE on LPS-treated AMs was significantly impaired by β2-adrenergic receptor (β2-AR) blockade or knockdown of histidine decarboxylase (HDC). Our in vivo experiments further demonstrated that salbutamol, a selective β2-AR agonist, upregulated SLC7A11 and GPX4 expression in septic mice and concurrently increased HDC expression in AMs. Furthermore, salbutamol alleviated lipid peroxidation, mitigated macrophage and lung tissue injury. These findings identify HDC/SLC7A11 as a potential axis involved in the neuroimmune regulation of ferroptosis in AMs, offering a potential therapeutic target for ARDS.