Figure 1.

Generation of Mtb-infected foamy macrophages during the formation of TB granulomas. (A) Composition of Mtb-infected foamy macrophages during TB pathogenesis. Alveolar macrophages initially infected by Mtb and translocated into the interstitial space to generate immune responses. With the extravasation of immune cells Mtb-infected alveolar macrophages differentiate into foamy macrophages. Infiltrated interstitial macrophages are also infected with Mtb and further differentiate into foamy macrophages. In the early stage of Mtb infection, macrophages show pro-inflammatory responses like M1 macrophages contributing to the restriction of Mtb survival. ESAT-6, a representative virulence factor of Mtb, polarizes these M1 macrophages into M2 macrophages to induce permissive responses in Mtb survival in the chronic stage of TB. These Mtb-infected foamy macrophages are hallmarks of TB granulomas; translocation of Mtb-infected foamy macrophages induces dissemination of Mtb. “aMΦ” and “iMΦ” indicate “alveolar macrophage” and “interstitial macrophage,” respectively. (B) Metabolic perturbation by Mtb infection to generate foamy macrophages with Mtb infection, lipid accumulation leads to the generation foamy macrophages via metabolic reprogramming. In the early stage of Mtb infection, excessive glycolysis with defective mitochondrial respiration contributes to de novo lipogenesis. Acetyl-CoA, a product of glycolysis, is metabolized to 3-hydroxybutyrate (3-HB) by ketogenesis to induce GPR109A signaling. De novo lipogenesis is also induced by signal transduction of GPR109A and mTORC1 signaling, which is induced by macrophage activation. Nuclear receptors, such as those in the PPAR and LXR family, also contribute to both metabolic reprogramming and immune responses. The expression of miR33 is induced by Mtb and miR33 inhibits lipid catabolism, supporting Mtb survival. Direct and indirect processes are indicated by arrows and dotted arrows, respectively.