Sphingosine-1-Phosphate Restrains Foamy Macrophage Formation and Modulates Inflammation in Multidrug-Resistant Tuberculosis

The high abundance of lipid loaded foamy macrophages in the granulomatous lesions is a key hallmark of advanced pulmonary tuberculosis. These macrophages serve as lipid-rich intracellular hiding niches that provides Mycobacterium tuberculosis (M.tb) survival and persistence during prolonged anti-tubercular treatment. Persistent infection and dysregulated inflammatory responses further complicate disease control, particularly in multidrug-resistant tuberculosis (MDR-TB), highlighting the need for host-directed therapeutic strategies. Our previous preclinical study demonstrated the therapeutic potential of the host sphingolipid sphingosine-1-phosphate (S1P) in reducing the mycobacterial burden in M.tb-infected animals, accompanied by enhanced pulmonary macrophage activation. To explore its translational potential, we investigated whether S1P modulates foamy macrophage formation in CD14 monocyte-derived macrophages from healthy donors and patients with MDR-TB. Notably, macrophages derived from patients with MDR-TB exhibited greater intracellular lipid droplet accumulation than those derived from healthy donors. This phenotype was further characterized by increased nitric oxide production and quantitative RT-PCR analysis of genes associated with immune regulation and lipid metabolism, including APOE, LDLR1, CLEC4E, CLEC7A, GP96, IL4, and IL13, which suggested a Th2-associated immunological bias in foamy macrophages. Collectively, these findings highlight the potential role of host sphingolipids in modulating foamy macrophage phenotypes and associated immunometabolic dysregulation, supporting further investigation of S1P as a host-directed therapeutic strategy against MDR-TB.