475-P: Peroxisome Proliferator-Activated Receptor Delta (PPARδ)—A Key Modulator in the Pathogenesis of Diabetes Mellitus and Mycobacterium Tuberculosis Comorbidity

The interplay between lipid metabolism and immune response in macrophages plays a pivotal role in various infectious diseases, notably tuberculosis (TB). Herein, we illuminate the modulatory effect of heat-killed Mycobacteria tuberculosis (HKMT) on macrophage lipid metabolism and its implications on the inflammatory cascade. Our findings demonstrate that HKMT potently activates the lipid scavenger receptor, CD36, instigating lipid accumulation. While CD36 inhibition mitigated lipid increase, it unexpectedly exacerbated the inflammatory response, marked by elevated CCL2 secretion. Intriguingly, this paradoxical effect was linked to an upregulation of PPARδ, distinct from its PPAR counterparts. Functional analyses employing PPARδ modulation revealed its central role in regulating both lipid dynamics and inflammation, suggesting it as a potential therapeutic target. Moreover, peripheral blood mononuclear cells (PBMCs) from diabetic individuals, a demographic at amplified risk of TB, exhibited heightened PPARδ expression and inflammation, further underscoring its pathological relevance. Targeting PPARδ in these cells effectively dampened the inflammatory response, offering a promising therapeutic avenue against TB, especially for those with diabetes.