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.

Sarcoidosis as an Autoimmune Disease

“…Linke and Wilson et al in their studies showed that activation of rapamycin (mTOR) complex 1 (mTORC1) in macrophages in mice leads to the progression and development of granulomas. It has also been shown in people with a progressive sarcoidosis (10,11).…”

“…Recently, a lot of attention has been paid to the role of T17 lymphocytes in the pathogenesis of sarcoidosis, a subgroup of CD4+ lymphocytes expressing IL-17A, which exhibit pro-inflammatory or anti-inflammatory properties in response to the local inflammatory milieu. It has been shown that in sarcoidosis granuloma macrophages express CCR20, causing the attraction of Tx17, and the expression of IL-23 causes a significant increase in the concentration of IL-17A (11,12). The ratio between Th17 and Treg cells probably determines the development and clinical course of sarcoidosis and can serve as a prognostic marker.…”

Immunometabolism of Leishmania granulomas

“…By contrast, IFNc-activated M1 macrophages efficiently channel internalized glucose into aerobic (or anaerobic) glycolysis and the pentose phosphate pathway for ATP and NADPH production, which in turn is required for production of NADPH oxidase 2-driven ROS. 15 Glycolytically derived pyruvate is still catabolized in the mitochondria, but in an impaired tricarboxylic acid cycle in which flux through isocitrate dehydrogenase and succinate dehydrogenase is blocked, leading to citrate/ isocitrate and succinate accumulation, and increased mitochondrial ROS via reverse electron transport. Citrate accumulation drives the synthesis of fatty acids as well as the antimicrobial metabolite, itaconate, while increased succinate levels stabilize HIF-1a, promoting the transcription of glycolytic enzymes and inflammatory cytokines (i.e.…”

“…75 This is in contrast to the situation for many other intracellular bacterial pathogens where increased autophagy results in their more efficient delivery to and degradation within the lysosome. 15,76 How AMPK is activated in Leishmania-infected macrophages remains unclear. Leishmania infection can lead to the efflux of ATP, 77 which would alter intracellular pools of AMP/adenosine diphosphate/ATP and potentially activate AMPK in the host cell.…”

Management of Sarcoidosis, a Selection of Topical Items Updating

“…Two of the four patients had significant improvements [ 24 ]. In the same vein, as activated macrophages are major players [ 25 , 26 ], McClain Caldwell et al hypothesized that human MSCs may reprogram alveolar macrophages from patients with sarcoidosis, and therefore could reverse the disease. In fact, unselected BAL cells, mainly macrophages, from sarcoidosis patients cocultured with mesenchymal stromal cells from healthy adults showed a switch from a pro-inflammatory to an anti-inflammatory pattern.…”