Immunometabolic reprogramming during mycobacterial infection: the role of DGAT1 in pulmonary inflammation

Tuberculosis (TB) remains a major public health challenge. In the lungs, Mycobacterium tuberculosis (Mtb) infects mainly macrophages and dendritic cells (DCs), and has the ability to promote lipid droplet (LD) accumulation, which favor bacterial persistence. In addition, LDs is a site for PGE₂ synthesis in BCG-infected macrophages, contributing to the inflammatory response. We investigated the role of diacylglycerol acyltransferase 1 (DGAT1)-mediated triacylglycerol (TAG) synthesis and the lipid mediator PGE₂ in DC response to mycobacterial infection. Bone marrow-derived DCs (BMDCs) from C57BL/6 mice (CEUA/IOC L010/2025) were differentiated with GM-CSF and infected with M. bovis BCG (MOI 5). BCG infection induced LD, TAG, and cholesterol ester accumulation, besides increased expression of lipid-related and proinflammatory genes. DGAT1 inhibition with A922500 reduced bacterial burden, LD accumulation, inos, il1b, and il6 expression, and cytokine secretion by infected-DCs. It also impaired the differentiation of IL-17-producing CD4⁺ T cells induced by infected DC supernatants, without altering DC activation markers. Notably, DGAT1 inhibition reduced PGE₂ secretion, while exogenous PGE₂ increased BCG burden, LD accumulation, cytokine release, and IL-17⁺ CD4⁺ T cell differentiation, reversing the effects of DGAT1 inhibition. In a murine model of intranasal BCG infection, we observed immune cell recruitment, metabolic reprogramming, and pulmonary granulomatous inflammation. However, DGAT1 inhibition did not alter pulmonary lesions assessed by microCT or immune cell populations evaluated by flow cytometry. Together, our findings identify an important role of DGAT1-mediated TAG synthesis and PGE₂ in LD accumulation, inflammatory responses, and T cell differentiation in BCG-infected DCs. Further in vivo studies are warranted to clarify the function of this pathway in LD accumulation and bacterial persistence, supporting its investigation as a potential target in TB.