Vitamin D Mitigates Klebsiella pneumoniae-Induced Pneumonia by Regulating Macrophage Polarization Through miR-223/ACSL3 Axis-Mediated Lipid Metabolism Reprogramming.

Abstract

BACKGROUND: Pneumonia caused by Klebsiella pneumonia (Kp) poses a significant risk to global public health. Vitamin D may reduce Kp infection risk and improve prognosis through immunomodulation. This study aimed to validate the treatment effects of Vitamin D and explore its regulatory mechanism in Kp-pneumonia. METHODS: In this study, a murine model of Kp-induced pneumonia and the MH-S alveolar macrophage cell line were used. Experimental assays included RT-qPCR, Western blot, TUNEL assay, ELISA, flow cytometry, dual-luciferase reporter assay, and metabolic analyses (FAO activity, Seahorse XF Glycolysis Stress Test). RESULTS: The results showed that vitamin D administration mitigated Kp-induced lung injury in mice. Mechanically, vitamin D alleviated inflammation by inhibiting macrophage M1 polarization. Vitamin D exerted its effects by upregulating miR-223, which directly targeted and suppressed ACSL3 expression. In macrophages, miR-223 overexpression alleviated macrophage apoptosis and M1 polarization by downregulating ACSL3. Knockdown of ACSL3 induced a shift to M2 polarization by enhancing FAO and suppressing glycolysis. In vivo, miR-223 overexpression alleviated Kp-induced lung injury by downregulating ACSL3. CONCLUSION: In conclusion, vitamin D induces macrophage M2 polarization by upregulating miR-223, which inhibits ACSL3, leading to lipid metabolism reprogramming. This novel axis represents a potential therapeutic strategy for Kp-induced pneumonia.