Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo

Nair, S and Sobotka, KS and Joshi, P and Gressens, P and Fleiss, B and Thornton, C and Mallard, C and Hagberg, H (2018) Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia.

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Abstract

Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro‐inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)‐expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS‐mediated Toll‐like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi‐1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift. Mdivi‐1 treatment also normalized the changes caused by LPS exposure, namely an increase in mitochondrial reactive oxygen species production and mitochondrial membrane potential as well as accumulation of key metabolic intermediate of TCA cycle succinate. Moreover, Mdivi‐1 treatment substantially reduced LPS induced cytokine and chemokine production. Finally, we showed that Mdivi‐1 treatment attenuated expression of genes related to cytotoxic, repair, and immunomodulatory microglia phenotypes in an in vivo neuroinflammation paradigm. Collectively, our data show that the activation of microglia to a classically pro‐inflammatory state is associated with a switch to glycolysis that is mediated by mitochondrial fission, a process which may be a pharmacological target for immunomodulation.