Bamgbose Temitayo T, Schilke Robert M, Igiehon Oluwakemi O, Nkadi Ebubechukwu H, Binwal Monika, Custis David, Bharrhan Sushma, Schwarz Benjamin, Bohrnsen Eric, Bosio Catharine M, Scott Rona S, Yurdagul Arif, Finck Brian N, Woolard Matthew D
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
Research Core Facility, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
J Immunol. 2025 Jan 1;214(1):85-103. doi: 10.1093/jimmun/vkae010.
Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function and polarization, which is crucial to the resolution of inflammation. The contribution of lipid synthesis to proinflammatory macrophage responses is well understood. However, how lipid synthesis regulates proresolving macrophage responses needs to be better understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that regulates lipid metabolism. We previously demonstrated that lipin-1 supports proresolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage proresolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis, the transport of citrate from the mitochondria, reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO mice and macrophages. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting proresolving macrophage function in response to proresolving stimuli.
巨噬细胞对于在炎症期间维持和恢复组织稳态至关重要。巨噬细胞的脂质代谢状态会影响其功能和极化，这对于炎症的消退至关重要。脂质合成对促炎巨噬细胞反应的贡献已得到充分理解。然而，脂质合成如何调节促消退巨噬细胞反应仍有待进一步了解。Lipin-1是一种具有转录共调节活性的磷脂酸磷酸酶，可调节脂质代谢。我们之前证明Lipin-1支持促消退巨噬细胞反应，在此，髓系相关的Lipin-1是炎症消退所必需的，但Lipin-1调节的细胞机制如何促进巨噬细胞促消退反应尚不清楚。我们证明巨噬细胞中Lipin-1的缺失导致游离脂肪酸、中性脂质和神经酰胺含量增加，以及乙酰辅酶A羧化酶的磷酸化增加。脂质合成第一步（即柠檬酸从线粒体的转运）的抑制降低了脂质含量，并恢复了Lipin-1基因敲除小鼠和巨噬细胞中的噬菌作用和炎症消退。我们的研究结果表明，巨噬细胞相关的Lipin-1抑制脂质合成，促进促消退巨噬细胞对促消退刺激的反应功能。
