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. 2019 Oct 4;10:2265. doi: 10.3389/fimmu.2019.02265

Figure 3.

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.