Abstract
Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro‐regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.
Highlights
Microglia are self-renewing, long-lived cells (Bruttger et al, 2015), which stem from a unique nonhaematopoietic yolk-sac-derived cell lineage, as indicated by elegant fate-mapping studies (Ginhoux et al, 2010; Kierdorf et al, 2013; Schulz et al, 2012)
Ha, Molon, & Kim, 2013; Ruppert et al, 2018) as well as in a mouse model of Alzheimer's disease (AD). Despite these findings offer a hopeful opportunity to advance novel cell-free therapeutic strategies that might prevail over the risks associated with the use of cells, a still unresolved issue is the molecular mechanism whereby the infused extracellular vesicles (EVs) reduce inflammation and rescue cognitive impairments in rodent models of neuroinflammatory diseases
DCA has been shown to shifts glucose metabolism toward the TCA cycle/oxidative phosphorylation in T cells in mice affected by EAE (Gerriets et al, 2015) and to promote a pro-regenerative microglia/macrophages phenotype in vitro and in a peripheral inflammation model (Kato et al, 2007)
Summary
Microglia are self-renewing, long-lived cells (Bruttger et al, 2015), which stem from a unique nonhaematopoietic yolk-sac-derived cell lineage, as indicated by elegant fate-mapping studies (Ginhoux et al, 2010; Kierdorf et al, 2013; Schulz et al, 2012). Consistent with this hypothesis, PPAR-γ signaling pathway, that is induced by agents which redirect microglia toward protective functions, promotes biogenesis of mitochondria and mitochondrial glucose metabolism, as mentioned above, and promote fatty acids beta oxidation, linking pro-regenerative microglia phenotype to fatty acid- and glucose-based energy production in mitochondria (Figure 2).
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