Abstract

Microglia, the resident immune cells of the central nervous system (CNS), exhibit dynamic metabolic reprogramming in response to chronic inflammation. We have previously uncovered that mitochondria play a key role in this process and that their dysfunction is linked with enhanced pro-inflammatory activity of microglia. However, the underlined molecular mechanism remained to be resolved. Here we show that the heightened expression of mitochondrial complex I (CI) genes and proteins characterise a specific cluster of persistently activated microglia in vivo. This unique cluster first appears during the acute phase of multiple sclerosis (MS)-like disease in mice, persists throughout the chronic phase, and can be found at the edge of chronic-active MS lesions in the brain. Importantly, interfering with CI function in microglia reduces their pro-inflammatory activation and secretion of neurotoxic reactive oxygen species. Focusing on this novel pathway and its relationship with mitochondrial function and metabolites, we identify new metabolic targets for therapeutic approaches aimed at reducing chronic CNS inflammation.

Affiliation and short bio

Microglia, the resident immune cells of the central nervous system (CNS), exhibit dynamic metabolic reprogramming in response to chronic inflammation. We have previously uncovered that mitochondria play a key role in this process and that their dysfunction is linked with enhanced pro-inflammatory activity of microglia. However, the underlined molecular mechanism remained to be resolved. Here we show that the heightened expression of mitochondrial complex I (CI) genes and proteins characterise a specific cluster of persistently activated microglia in vivo. This unique cluster first appears during the acute phase of multiple sclerosis (MS)-like disease in mice, persists throughout the chronic phase, and can be found at the edge of chronic-active MS lesions in the brain. Importantly, interfering with CI function in microglia reduces their pro-inflammatory activation and secretion of neurotoxic reactive oxygen species. Focusing on this novel pathway and its relationship with mitochondrial function and metabolites, we identify new metabolic targets for therapeutic approaches aimed at reducing chronic CNS inflammation.

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