DGAT1-Mediated Lipid Droplet Accumulation Promotes M. bovis BCG Persistence on Dendritic Cells by Acting as an Immunoinflammatory Platform Through PGE2 Signaling

Abstract Tuberculosis remains a major global health challenge. In the lungs, dendritic cells (DC)s are among the primary cells infected by Mycobacterium tuberculosis (Mtb), playing a role in initiating adaptive immunity. Mtb exploits host lipid metabolism for survival, particularly using triacylglycerol (TAG) as a carbon source during latency. 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)E 2 . Bone marrow-derived DCs (BMDC)s from C57BL/6 infected with M. bovis BCG exhibited increased lipid droplet (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, PGE 2 secretion was also reduced by inhibition of DGAT-1. Given PGE 2 ’s established role in TB immunity and T cell differentiation, exogenous PGE 2 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 PGE 2 signaling are critical modulators of LD formation and the inflammatory response in DCs during mycobacterial infection.