Table 1.

Epithelioid and foamy macrophages in TB granulomas.

Cell Type	Location in granuloma	Role in mycobacterial infection	Stimulus that drives production
Epithelioid macrophages	Surrounding the necrotic center and interspersed in the cellular rim (34)	Depletion leads to increased intracellular bacillary numbers (35) whereas excessive formation “walls off” infection site from other immune cells and antibiotics (36, 37)	IL-4 activation of STAT6, which mediates expression of E-cadherin, adhesion molecule that is crucial in transforming cytoskeletal structure of epithelioid macrophages through production of adherens junctions, desmosomes, & tight junctions (11, 35, 37)
Foamy macrophages	Surrounding the necrotic center; rarely found in non-necrotic granulomas (32)	Contributes to caseous necrosis (by discharging intracellular lipids & Mtb) & have less bactericidal/phagocytic compared to other macrophages due to fat accumulation, creating long-term persistence of Mtb in these cells (31, 38); fat accumulation occurs due to ESX-1 driven metabolic shift from glycolysis to ketogenic pathway synthesis, inducing expression of G-protein coupled receptor GPR109A which inhibits lipolysis (39) ( Figure 3 ); fat accumulation decreases autophagy due to lower expression of lactate (byproduct of glycolysis), which normally increases autophagy by lactylation of class III phosphatidylinositol 3 kinase) (39–42); reduced autophagy further attenuates glycolysis and ketogenic pathway (i.e., oxidative phosphorylation), the latter via autophagy mediated metabolism of triglycerides into fatty acids, which are then broken down into acetyl Co A in the mitochondria for ATP production (43–45).	Mtb derived oxygenated mycolic acids bind to host lipid sensing nuclear receptors PPARγ and TR4, inducing production of host derived LDL receptors (scavenger receptor A and CD36) (31, 38, 46, 47); these receptors bind and mediate influx of host derived LDL intracellularly ( Figure 3 ); ESX-1 drives foamy macrophage formation in M. marinum-zebrafish model (48); IL-10 also shown to induce differentiation to foamy macrophages (49)

ESX-1, ESAT-6 protein family secretion system (ESAT-6, 6 KDa early secretory antigenic target); IL-4, interleukin-4; LDL, low density lipoprotein; PPARγ, peroxisome proliferator-gamma; TR4, testicular receiver 4.