AR Deficiency Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Macrophage M1 Polarization and Inflammatory Cytokine Secretion

Acute lung injury (ALI) constitutes a major public health concern, with sepsis contributing to up to 50% of ALI cases in the ICU. Androgen receptor (AR) plays a crucial role in immunoregulation. Our study aimed to explore the role of AR and the underlying regulatory mechanisms of AR signaling in septic ALI. We assessed the role of AR in a septic ALI model by manipulating AR expression through orchiectomy, AR knockout, and enzalutamide treatment. Lung injury was evaluated by HE staining and measuring pulmonary vascular leakage. Inflammatory cell infiltration and inflammatory mediator levels were assessed through Immunofluorescence staining and western blot. Additionally, Weighted Gene Co-expression Network Analysis (WGCNA), lentiviral vector, chromatin immunoprecipitation and co-immunoprecipitation were used to elucidate the molecular mechanisms by which AR regulates the secretion of inflammatory cytokines in alveolar macrophages. Male mice exhibited more severe lung injury than female mice in sepsis-induced lung injury. Orchiectomy, AR knockout and enzalutamide treatment suppressed AR activity and significantly alleviated lung injury. AR promotes Fkbp5 expression and NF-κB signaling pathway, thereby enhancing the expression of iNOS and IL-6 in macrophages. Moreover, AR transcription in alveolar macrophages is regulated by hypoxia-inducible factor 1α (HIF1α) signaling. Our study elucidated that inhibiting AR decreases the secretion of inflammatory cytokines in alveolar macrophages and mitigates septic ALI, providing a novel therapeutic approach for septic ALI.