Extracellular Succinate Modulates Neuroimmune Responses in a Murine Microglial Cell Line.

Neuroinflammation mediated by reactive microglia, the immune cells of the brain, contributes to numerous neuropathologies. Damage-associated molecular patterns (DAMPs), released from stressed or damaged cells, are implicated in neuroinflammation. Succinate, a tricarboxylic acid cycle intermediate, can accumulate intracellularly and be released into the extracellular space where it may function as a DAMP-like molecule. However, its specific roles in central nervous system (CNS) neuroimmune responses, particularly when acting extracellularly, remain largely unexplored. This study utilizes cell membrane-impermeable disodium succinate to model extracellular action and cell-permeable diethyl succinate to assess the intracellular activity of this metabolite in cell culture models. We demonstrate that extracellular disodium succinate significantly reduces the secretion of pro-inflammatory cytokines tumor necrosis factor-α (TNF) and interleukin (IL)-6, and lowers neurotoxic and phagocytic activities of immune-stimulated BV-2 murine microglia. It also rescues lipopolysaccharide (LPS)-induced decreases in mitochondrial respiration in human peripheral blood mononuclear cells (PBMCs) used as microglia models, which correlates with its actions on phagocytosis. In contrast, while intracellular diethyl succinate reduces TNF and IL-6 secretion, it does not reduce BV-2 microglia toxicity towards murine NSC-34 neuronal cells, indicating location-dependent effects. These results support extracellular succinate as a novel CNS DAMP with a predominantly anti-inflammatory action on microglia.