DGAT1-mediated lipid droplet accumulation promotes M. bovis BCG persistence on dendritic cells by acting as an immunoinflammatory platform through PGE₂ signaling

Despite global control efforts, tuberculosis remains a major public health challenge. In the lungs, dendritic cells (DCs) are among the first cells infected by members of the Mycobacterium tuberculosis complex (MTC), where they link innate and adaptive immunity. MTC exploits host lipid metabolism, particularly triacylglycerol (TAG) stored in lipid droplets (LDs), to support intracellular survival and persistence. While the role of LDs has been extensively investigated in macrophages, their function in DCs remains poorly understood. Here, we investigated the role of TAG synthesis in DC activation and bacterial burden during mycobacterial infection, with a focus on diacylglycerol acyltransferase-1 (DGAT1) and the eicosanoid prostaglandin (PG)E2. Bone marrow-derived DCs (BMDC)s from C57BL/6 mice infected with M. bovis BCG exhibited increased LD formation, TAG and cholesterol ester accumulation, and upregulation of the transcription of lipid-related and proinflammatory genes. Pharmacological inhibition of DGAT1 with A922500 reduced bacterial burden, LD accumulation, and mRNA expression of Nos2, Il1b, and Il6, as well as the secretion of IL-1β, IL-6, IL-10, IL-23, and TNF-α. However, DGAT1 inhibition did not alter the expression of DC activation markers. Interestingly, PGE2 secretion was also reduced by inhibition of DGAT-1. Given PGE2’s established role in TB immunity and T cell differentiation, exogenous PGE2 was added to infected DCs, leading to an increase in bacterial load, cytokine release, and LD accumulation, reversing the effects of DGAT1 inhibition. These findings indicate that TAG synthesis via DGAT1 and PGE2 signaling are critical modulators of LD formation and the inflammatory response in DCs during mycobacterial infection.