Intersection of lipid metabolism and the innate immune response to mycobacterial infection

Intracellular pathogens survive by evading the host immune system and accessing host metabolic pathways to obtain nutrients for their growth. Mycobacterium leprae, the causative agent of leprosy, is the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Here we show the importance of lipid metabolism in mycobacterial infection and regulation of the innate immune response. In the lesions of patients with the lepromatous, or disseminated, form of human leprosy (L-lep), there was preferential expression of host lipid metabolism genes and host-derived oxidized phospholipids. Mycobacterial infection of macrophages in vitro induced an accumulation of oxidized phospholipids that inhibited innate immune responses. These data suggest that the link between host lipid metabolism and innate immune defense contributes to the pathogenesis of microbial infection.;To further elucidate mechanism of oxidized phospholipids modulation of the immune response, we screened for the receptor that binds oxidized 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine (OxPAPC), which can not only activate endothelial cells to bind monocytes, but also alter the innate immune response in monocyte-derived cells by decreasing the proinflammatory cytokine TNFalpha and increasing the anti-inflammatory cytokine IL-10. The prostaglandin E2 receptor EP2 was identified to bind OxPAPC and stimulation replicated the effects on the immune response. These results provide a mechanism for how oxidized phospholipids trigger EP2 to alter the innate immune response.;Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. Here we found that IL-10 induced the phagocytic pathway, resulting in phagocytosis of mycobacteria and oxidized lipids, while IL-15 only induced the vitamin D-dependent antimicrobial pathway. The differential regulation of macrophage functional programs was reflected in the leprosy lesions: the phagocytosis pathway was prominent in the disseminated form whereas the antimicrobial pathway predominated in the self-limited form of the disease. These data indicate that macrophage programs for phagocytosis of oxidized lipids and mycobacteria versus antimicrobial responses are distinctly regulated in innate immunity in bacterial infections.