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Extracellular Succinate Modulates Neuroimmune Responses in a Murine Microglial Cell Line
Samantha C Y Yudin1, Kimberly Day2, Erica Y Scott1
1Department of Biology, Faculty of Science, University of British Columbia Okanagan Campus, Kelowna, BC V1V 1V7, Canada.
Abstract:
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.
Insights
Extracellular succinate acts as a novel damage-associated molecular pattern (DAMP) that reduces neuroinflammation. This study shows extracellular succinate has anti-inflammatory effects on microglia, unlike intracellular succinate.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Neuroinflammation, driven by reactive microglia, is central to neuropathologies.
- Damage-associated molecular patterns (DAMPs) trigger neuroinflammation.
- Succinate's role as an extracellular DAMP in the central nervous system (CNS) is largely unknown.
Purpose of the Study:
- To investigate the specific roles of extracellular and intracellular succinate in CNS neuroimmune responses.
- To determine if succinate acts as a DAMP modulating microglial activity.
Main Methods:
- Utilized cell membrane-impermeable disodium succinate for extracellular modeling and cell-permeable diethyl succinate for intracellular modeling in cell culture.
- Assessed pro-inflammatory cytokine secretion (TNF-α, IL-6), microglial neurotoxicity, phagocytosis, and mitochondrial respiration.
Main Results:
- Extracellular disodium succinate reduced pro-inflammatory cytokine secretion and microglial neurotoxic/phagocytic activities.
- Extracellular succinate rescued lipopolysaccharide (LPS)-induced mitochondrial respiration deficits in human peripheral blood mononuclear cells (PBMCs).
- Intracellular diethyl succinate reduced cytokine secretion but did not affect microglial neurotoxicity, indicating location-dependent effects.
Conclusions:
- Extracellular succinate functions as a novel CNS DAMP.
- Succinate exhibits predominantly anti-inflammatory actions on microglia when acting extracellularly.
