Page 24 - 2018_10-Haematologica-web

F. Grimolizzi and L. Arranz et al.
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Figure 2. Dual role for succinate as pro- and anti-inflammatory signal. (A) Succinate as pro-inflammatory signal. Toll-like receptor (TLR) activation in macrophages causes intracellular succinate accumulation and release. In the cytosol, succinate functions as competitive inhibitor for prolyl hydroxylase domain (PHD) proteins, promoting stabilization of hypoxia-inducible factor-1α (HIF-1α), that in turn leads to pro-inflammatory interleukin-1b (IL-1b) production.3 Activation of interleukin-1 receptor (IL-1R) increases G protein-coupled receptor 91 (GPR91) expression, and extracellular succinate interacts with GPR91. This results in pseudohypoxia and IL-1b production, independent of HIF.34 (B) Succinate as anti-inflammatory signal. M1 inflammatory macrophages release succinate, which activates GPR91 on neu- ral stem cells increasing the expression in vitro of prostaglandin E2 (PGE2) and members of the sodium-coupled citrate (SLC) family of transporters 13 (i.e. SLC13A3 and SLC13A5). In vivo, the most prominent anti-inflammation mechanism is succinate scavenging by SLC13 transporters. This reduces IL-1b and succinate extra- cellular levels, and promotes a shift in macrophage polarity from pro-inflammatory (in green) to anti-inflammatory phenotype (in blue).20 LPS: lipopolysaccharide; VHL: von Hippel-Lindau protein; Ub: ubiquitin.
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haematologica | 2018; 103(10)