ASM promotes macrophage glycolysis and M1 polarization by activating the mTOR/HIF-1α pathway in neutrophilic asthma

Background: Neutrophilic asthma is a complex asthma phenotype characterized by neutrophil recruitment to the airways and M1-macrophage polarization. While the relationship between sphingolipid metabolism, particularly acid sphingomyelinase (ASM) which hydrolyzes sphingomyelin to ceramide, and asthma has been proposed, the exact role of ASM in regulating macrophage polarization are still unknown. Methods and Objectives: We analysed the expression of ASM and M1 macrophage in asthma patients and healthy controls. We generated Asm-/- mice and induced neutrophilic asthma. In vitro, we induced M1 polarization in THP-1 cells and knocked down Asm, followed by transcriptomic analysis of differential pathways and validation. Results: We found that the expression of ASM and the proportion of M1 macrophages were significantly increased in sputum cells from neutrophilic asthma patients and in the lung tissue of neutrophilic asthma mice compared to controls. Asm-/- mice exhibited reduced lung tissue inflammation and fewer M1 macrophages. In vitro, knockdown of Asm in THP-1 cells significantly suppressed the proportion of M1 macrophages. RNA sequencing results indicated that the glycolysis-related pathways and the mTOR/HIF-1α pathways were significantly downregulated in the lung tissue of Asm-/- mice. Further mechanistic studies suggested that ASM activates the mTOR/HIF-1α pathway, which in turn upregulates macrophage glycolysis and promotes M1 polarization. Conclusion: ASM activates mTOR/HIF-1α pathway and promote macrophage glycolysis and M1 polarization, exacerbating the inflammatory response in neutrophilic asthma.