Traumatic brain injury (TBI) is a major health problem with high rates of mortality and morbidity worldwide. The response of the brain to TBI is orchestrated by a number of cytokines, including interleukin‐6 (IL‐6). IL‐6 is a major cytokine in the central nervous system and it is produced by different cells, such as neurons, glial cells, and endothelial cells. Since glial cells are one of the most important sources and targets of IL‐6, we have examined the role of microglia‐derived IL‐6 in normal conditions and following a model of TBI, cryolesion of the somatosensorial cortex. To this end, tamoxifen‐inducible microglial IL‐6‐deficient (Il6ΔMic, using Cx3cr1
CreER model) mice and control (Il6lox/lox) mice were used. In normal conditions, microglial IL‐6 deficiency reduced deambulation and exploratory behavior and decreased anxiety in a sex‐dependent manner. The transcriptome profile following cryolesion was dramatically altered 1 day post‐lesion in Il6ΔMic compared with Il6lox/lox mice. However, the phenotype of Il6ΔMic mice was less compromised in the following days, suggesting that compensatory mechanisms are at play.
Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.
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