Microglia, the brain's resident immune cells, constantly monitor their environment for signs of tissue damage or pathogens. Upon activation by stimuli like lipopolysaccharide (LPS), microglia undergo metabolic changes and release pro-inflammatory mediators. However, variations between human and rodent microglia, as well as differences between in vitro and in vivo conditions, likely influence microglial cellular functions and their responses to stimulation. In the present study, we compared several rodent and human model systems, including cell lines, primary cultures, induced pluripotent stem cell (iPSC)-derived cultures, and acutely isolated microglia, and revealed striking differences in LPS-induced metabolic changes and nitric oxide (NO) production. Using the murine microglial cell line BV-2, we demonstrated that NO was critical for restricting metabolism to glycolysis by blocking oxidative phosphorylation. In contrast, human iPSC-derived microglia and acutely isolated microglia from intraperitoneally injected rats maintained mitochondrial respiration upon LPS activation and did not show significant NO production and inducible nitric oxide synthase (iNOS) expression, respectively. Furthermore, we found that NO was not required for the increase in glycolysis rate or the release of pro-inflammatory cytokines upon LPS stimulation. Our results suggest that glycolysis is essential for microglial activation and cytokine production irrespective of NO production. However, the specific metabolic pathways involved may differ between species and experimental conditions. Understanding these differences is crucial for developing effective therapeutic strategies targeting microglial dysfunction in neurological diseases.
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