Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease

Abstract

Metabolic reprogramming is rapidly gaining appreciation in the etiology of immune cell dysfunction in a variety of diseases. Tuberculosis, schistosomiasis, and sarcoidosis represent an important class of diseases characterized by the formation of granulomas, where macrophages are causatively implicated in disease pathogenesis. Recent studies support the incidence of macrophage metabolic reprogramming in granulomas of both infectious and non-infectious origin. These publications identify the mechanistic target of rapamycin (mTOR), as well as the major regulators of lipid metabolism and cellular energy balance, peroxisome proliferator receptor gamma (PPAR-γ) and adenosine monophosphate-activated protein kinase (AMPK), respectively, as key players in the pathological progression of granulomas. In this review, we present a comprehensive breakdown of emerging research on the link between macrophage cell metabolism and granulomas of different etiology, and how parallels can be drawn between different forms of granulomatous disease. In particular, we discuss the role of PPAR-γ signaling and lipid metabolism, which are currently the best-represented metabolic pathways in this context, and we highlight dysregulated lipid metabolism as a common denominator in granulomatous disease progression. This review therefore aims to highlight metabolic mechanisms of granuloma immune cell fate and open up research questions for the identification of potential therapeutic targets in the future.

Keywords: granuloma; immunometabolism; macrophage; sarcoidosis; schistosomiasis; tuberculosis.

Figure 1

Mycobacterium tuberculosis elicits a biphasic immunometabolic response in host macrophages. (A) Monocyte-derived interstitial macrophages, and macrophages during the acute phase response to Mtb infection, adopt an M1-like phenotype characterized by a Warburg-like switch in metabolism. Enhanced HIF-1α-mediated glycolytic activity and glucose uptake results in the rapid generation of ATP to support the pro-inflammatory reaction, which occurs simultaneous to the increased generation and export of lactate. Concomitant reductions in OXPHOS, PDC, and FAO occur as result of two consecutive breaks in the TCA cycle at the conversion of citrate to α-ketoglutarate (α-KG) and succinate to fumarate, as well as the down-regulation of the TCA cycle enzymes involved in these reactions: IDH and SDH, respectively. Accumulation of the TCA intermediate citrate as a result of the first breakpoint in the cycle (citrate to α-KG) leads to the generation of itaconate, which inhibits SDH directly as well as Mtb survival by blocking bacterial isocitrate lyase and consequently fatty acid catabolism by the bacteria. Accumulation of succinate as a result of the second break in the TCA cycle (succinate to fumarate), as well as direct inhibition of SDH by itaconate, stabilizes HIF-1α and its pro-inflammatory activity. The uptake and metabolism of arginine are additionally increased, promoting the production of NO via iNOS/NOS2. Together, these events culminate in the generation of a potent antimycobacterial response marked by the generation of pro-inflammatory cytokines, ROS/RNS and bioactive lipids, which in parallel with increased glycolysis and reduced FAO, result in Mtb growth control. (B) Tissue-resident alveolar macrophages, and macrophages entering an adaptation/resolution phase during chronic Mtb infection, adopt an M2-like phenotype characterized by an intact TCA cycle and enhanced FAO-driven OXPHOS, with a concomitant reduction in glycolytic activity and glucose uptake. This coincides with increased expression and activity of Pgc1β, which promotes mitochondrial biogenesis and oxidative metabolism. During the infection process, Mtb augments PPAR-γ expression, resulting in a weakened inflammatory response, as well the formation and accumulation of lipid droplets within the cell, thus providing a favorable niche for the growth and survival of Mtb. PPAR-α can also be activated in macrophages during Mtb infection, which enhances autophagic, lysosomal and phagosomal processes that contribute to Mtb growth control. Likewise, cytosolic AMPK, while enhancing OXPHOS and FAO, also promotes antimycobacterial autophagy, and is therefore directly inhibited by Mtb. mTORC1, induced by Mtb, supports bacterial survival by promoting lipogenesis and blocking autophagy, potentially due to its interactions with PPAR-γ and PPAR-α, respectively. Dotted lines represent interactions inferred from the literature. Up- and downregulation are indicated by blue and red, respectively. Acetyl-CoA, acetyl coenzyme A; AMPK, adenosine monophosphate activated protein kinase; ATP, adenosine triphosphate; FAO, fatty acid oxidation; GLUT, glucose transporter; HIF-1α, hypoxia-inducible factor 1-alpha; IDH, isocitrate dehydrogenase; IFN-γ, interferon gamma; IL, interleukin; iNOS, inducible nitric oxide synthase; MCT, monocarboxylate transporter; Mtb, Mycobacterium tuberculosis; mTORC1, mammalian/mechanistic target of rapamycin complex 1; NF-κB, nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells; NO, nitric oxide; NOS2, NO synthase 2; OXPHOS, oxidative phosphorylation; PDC, pyruvate dehydrogenase complex; Pgc1β, peroxisome proliferator-activated receptor gamma coactivator 1-beta; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; RNS, reactive nitrogen species; SDH, succinate dehydrogenase; TCA, tricarboxylic acid.

Figure 2

Periovular granuloma macrophages in schistosomiasis assume an M2-like phenotype with altered lipid metabolism. Antigens from Schistosoma mansoni eggs (and adults) activate PPAR-γ signaling. Some Schistosoma products have also been shown to inhibit signaling by the FAO inducer, PPAR-α. PPAR-γ contributes to an M2 phenotype by upregulating M2 markers including arginase-1. It also promotes expression of the scavenger receptor CD36, which takes up free fatty acids and oxidized LDL cholesterol. In contrast, PPAR-γ inhibits oxLDL cholesterol uptake via the LOX-1 receptor. S. mansoni itself also attenuates LOX-1 by decreasing ApoC1 and ApoC3 via an unknown mechanism. Additionally, S. mansoni infection also leads to an upregulation of CD14, which has in turn been shown to promote uptake of oxLDL and other lipids in macrophages. HDL cholesterol efflux may also be increased through the PPAR-γ-mediated upregulation of ABCA1 and ABCG1, contributing to an anti-atherogenic phenotype. Up- and downregulation are indicated by blue and red, respectively. ABC, adenosine triphosphate-binding cassette transporter; Apo, apolipoprotein; CD, cluster of differentiation; FAO, fatty acid oxidation; HDL, high-density lipoprotein; LOX-1, lectin-like oxidized low-density lipoprotein receptor 1; oxLDL, oxidized low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor.

Figure 3

Metabolic signaling and chronic inflammation in sarcoidosis disease progression. The etiological trigger of sarcoidosis remains unknown; however, environmental and genetic factors have been proposed. Deficiency of PPAR-γ and its transcriptional coactivator Ppargc1α in alveolar macrophages has been implicated in disease severity, resulting in the alleviation of NF-κB transrepression and enhancement of a pro-inflammatory phenotype. Reduced expression of the cholesterol and lipid transporters ABCG1 and ABCA1 and disruption of LXR-α signaling, which are involved in the maintenance of lipid homeostasis by PPAR-γ, leads to lipid accumulation in macrophages. NF-κB can also be activated via TLR2 signaling in response to increased levels of SAA, leading to the generation of pro-inflammatory molecules. SAA can reduce serum HDL cholesterol and ApoA1, increasing the risk of atherosclerosis in sarcoidosis patients. However, SAA can also work with sPLA to promote the enzymatic digestion and removal of cell debris, which contributes to the anti-inflammatory processes of wound healing and tissue repair. In sarcoid-like granuloma macrophages, mTORC1 promotes cell proliferation and inhibits apoptosis via CDK4-dependent enhancement of glycolysis and OXPHOS. mTORC1 also directly promotes the function of HIF-1α, which in turn contributes to glycolysis and inflammation. An M2-like phenotype in sarcoid granulomas has additionally been reported, involving CCL18, IL-13, and IL-17. Up- and downregulation are indicated by blue and red, respectively. Dotted lines represent interactions inferred from the literature. ABC, adenosine triphosphate-binding cassette transporter; Apo, apolipoprotein; CCL18, chemokine (C-C motif) ligand 18; CDK, cyclin-dependent kinase; HDL, high-density lipoprotein; HIF-1α, hypoxia-inducible factor 1-alpha; IL, interleukin; GLUT, glucose transporter; LXR, liver X receptor; mTORC1, mammalian/mechanistic target of rapamycin complex 1; NF-κB, nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells; OXPHOS, oxidative phosphorylation; PPAR, peroxisome proliferator-activated receptor; SAA, serum amyloid A; sPLA, secretory phospholipase A; TLR, toll-like receptor.