Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Abstract

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment

“…Yet, IL-1β is associated with tumorigenesis by a direct induction of EMT [8]. Additionally, an anti-inflammatory role of succinate on macrophages has been described recently, decreasing CD86, CD80 and inducible nitric oxide (iNOS) expression and secretion of IL-6, tumor necrosis factor (TNF) and NO independently of GPR91 [68]. However, whether this mechanism also plays a role in TAM generation in vivo remains to be established.…”

Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses

“…Previous studies have identified immunosuppressive roles for α-ketoglutarate. Interleukin-4 (IL-4)-induced anti-inflammatory macrophages have been shown to accumulate the metabolite α-ketoglutarate [58]. It was also found that α-ketoglutarate suppresses the activation of pro-inflammatory macrophages (e.g., IL-1β expression) and supports endotoxin tolerance after activation [26,59].…”

“…PHD1 inactivates IKK-β kinase via hydroxylation of Pro191, which, in turn, phosphorylates IκB-α, activating NF-κB [57,60]. α-Ketoglutarate inhibits stabilization of hypoxia-induced factor (HIF)-1α, a transcription factor inducing expression of immune-related genes (e.g., pro-inflammatory cytokines [61], glycolytic enzymes, and glucose transporters [62][63][64][65]) by donating an electron to HIFspecific PHD for prolyl hydroxylation leading to the degradation of HIF-1α [28,53,58,62,[66][67][68][69][70]. In line with this, reduced levels of α-ketoglutarate were found to abolish PHD activity [16,53,69,71,72].…”

“…LPS induces succinylation, which impacts macrophage function. LPS-induced hyper-succinylation of lysine 311 on pyruvate kinase M2 (PKM2), a key glycolytic enzyme interacting with HIF-1α and regulating aerobic glycolysis in macrophages, inhibits its pyruvate kinase activity by promoting its tetramer-to-dimer transition and induces IL-1β secretion [58,90,92,93]. LPS decreases the expression of the desuccinylase SIRT5 [28,78].…”

“…Succinylation of certain proteins is found to drive immunosuppression in proinflammatory macrophages. Thus, the inflammatory effects of succinylation may be context-dependent and inducing various immunologic responses [28,58,97].…”