What is the role of succinate in driving inflammation through gene expression?

From the Guidelines

Succinate plays a crucial role in driving inflammation through its interaction with the succinate receptor GPR91, leading to the activation of pro-inflammatory pathways and the production of inflammatory cytokines. This is evident from the fact that elevated succinate levels can stabilize HIF-1α by inhibiting prolyl hydroxylase enzymes, promoting inflammatory gene expression even under normoxic conditions 1. The succinate-GPR91 pathway represents a critical link between cellular metabolism and immune function, with succinate serving as a danger signal that alerts the immune system to tissue damage or metabolic stress.

Key Points

• Succinate accumulation can act as both an intracellular metabolic signal and an extracellular signaling molecule, triggering pro-inflammatory pathways 1
• The succinate-GPR91 pathway is involved in the activation of HIF-1α, leading to increased production of inflammatory cytokines such as IL-1β 1
• Elevated succinate levels are often associated with conditions like obesity, diabetes, and autoimmune disorders, where the metabolic-inflammatory axis is particularly important 1
• The role of succinate in driving inflammation is supported by studies on the molecular genetics of HPP syndromes, which highlight the importance of SDH genes in regulating cellular metabolism and preventing tumor growth and metastasis 1

Clinical Implications

• Understanding the role of succinate in driving inflammation can inform the development of novel therapeutic strategies for conditions like obesity, diabetes, and autoimmune disorders
• The succinate-GPR91 pathway may represent a potential target for the treatment of inflammatory diseases, with the goal of reducing succinate levels and mitigating its pro-inflammatory effects
• Further research is needed to fully elucidate the mechanisms by which succinate drives inflammation and to explore the potential clinical applications of this knowledge 1

From the Research

Succinate's Role in Inflammation

• Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles beyond metabolism in both physiological and pathological conditions 2.
• It plays key dual roles during inflammatory responses, leading to net inflammation or anti-inflammation depending on factors like the cellular context 2.
• Succinate links metabolism to processes like gene expression and intercellular communication, and it is involved in the formation and elimination of reactive oxygen species 3.

Succinate and Gene Expression

• Succinate induces IL-1β through HIF-1α, which is an important target in inflammation 4.
• Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, leading to increased IL-1β production during inflammation 4.
• Serum succinate levels and blood IL-1β gene expression were increased in ADPKD patients with high levels of HIF-1α gene expression 5.

Mechanisms of Succinate-Induced Inflammation

• Glutamine-dependent anaplerosis is the principal source of succinate, although the 'GABA shunt' pathway also has a role 4.
• Succinate dehydrogenase pathway is involved in the activation of HIF-1α during acute lung injury induced by trauma/hemorrhagic shock 6.
• Inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β, suggesting a link between glycolysis and succinate-induced inflammation 4.