Trained immunity attenuated acute lung injury by activating alveolar macrophages via AKT2-PDK1 axis-mediated metabolic reprogramming

BACKGROUND: Acute lung injury (ALI) is a life-threatening clinical syndrome typically triggered by sepsis or severe trauma lacking effective treatment options. Alveolar macrophages (AMs), representing the most abundant immune cell population in pulmonary tissue, exhibited functional abnormalities that were closely associated with ALI pathogenesis. Notably, elevated pulmonary lactate secretion served not only as a characteristic pathological feature of ALI but also participated in disease progression through modulation of AMs activity. Trained immunity was found to activate innate immune cells including macrophages, regulating metabolic adaptations that alleviated ALI, though the precise mechanisms remained unclear. METHODS: We used β-glucan and LPS to establish both in vivo and in vitro models of trained immunity and ALI, enabling investigation of trained immunity effects on AMs immunoregulatory functions. RESULTS: The results demonstrated that trained immunity effectively attenuated ALI severity by up-regulating glycolytic activity in AMs, thereby potentiating their immune responsiveness, and primarily enabled alveolar macrophages to sustain immune responses in high-lactate environments through the AKT2-PDK1 axis, an effect that was abolished by relevant inhibitors. CONCLUSIONS: We concluded that β-glucan induced trained immunity could enhance alveolar macrophage immune activity and improve lactate metabolic tolerance, offering a novel therapeutic approach for acute lung injury (ALI).