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

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.

mTOR‐mediated metabolic reprogramming shapes distinct microglia functions in response to lipopolysaccharide and ATP

“…In the present study, we uncover distinct metabolic adaptations in primary cultured microglia treated with proinflammatory PAMP, immunomodulatory cytokine, and DAMP molecules. Importantly, we find that ATP, one of the well‐known DAMPs, enhanced both glycolysis and OXPHOS in microglia, which is distinct from the glycolytic induction and OXPHOS suppression in PAMP‐treated proinflammatory microglia and macrophages (Biswas & Mantovani, ; Huang et al, ;Nair et al, ; Orihuela et al, ). In turn, reprogramed metabolic states contribute to the production of different cytokines and distinct immunoresponses in microglia under different conditions.…”

“…Transcriptomic analysis shows that microglia express full set of genes required for both glycolytic and oxidative energy metabolism (Freilich et al, 2013). At quiescent state, microglia likely use primarily OXPHOS for ATP production (Chenais, Morjani, & Drapier, 2002;Moss & Bates, 2001); however, they quickly switch to aerobic glycolysis upon LPS stimulation (Nair et al, 2019;Orihuela et al, 2016). In mouse AD and seizure models, substantial changes in genes engaged in lipid and glucose metabolism were observed in activated microglia (Bosco et al, 2018;Rangaraju et al, 2018;Ulland et al, 2017), suggesting potential changes in microglia metabolism in these diseases.…”

“…Microglia treated by LPS adopt an M1‐assocatiated proinflammatory phenotype, and adopt the M2‐related anti‐inflammatory and immunomodulatory phenotype upon IL‐4 treatment (Cao & He, ; Qin et al, ; Tang & Le, ). Metabolically, LPS‐treated microglia also upregulate glycolysis and downregulate OXPHOS to support the proinflammatory responses (Nair et al, ; Orihuela, McPherson, & Harry, ). Due to the presence of the blood–brain barrier (BBB), however, microglia in the brain parenchyma are more frequently activated by the damage‐associated molecular patterns (DAMPs) than by the pathogen‐associated molecular patterns (PAMPs), for example, LPS.…”

“…Microglia treated by LPS adopt an M1-assocatiated proinflammatory phenotype, and adopt the M2-related anti-inflammatory and immunomodulatory phenotype upon IL-4 treatment (Cao & He, 2013;Qin et al, 2019;Tang & Le, 2016). Metabolically, LPS-treated microglia also upregulate glycolysis and downregulate OXPHOS to support the proinflammatory responses (Nair et al, 2019;Orihuela, McPherson, & Harry, 2016).…”

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

“…Conversely, the control iPS-Mg responded to the pro-inflammatory stimuli in a similar manner to recent studies that have employed primary microglia cultures. 26,45 Interestingly, when we blocked glycolysis prior to LPS/IFNγ exposure, only control and R47H het iPS-Mg were able to increase energy demand through enhanced oxidative phosphorylation. These data suggest a less dramatic loss of energy production in the AD-associated risk variant compared with the more severe NHD mutations.…”