mTOR-dependent translation amplifies microglia priming in aging mice

Abstract

Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in aging and neurodegeneration.

Chronic stress primes innate immune responses in mice and humans

“…Notably, many of the monocytic inflammatory pathways we found to be upregulated in stress-primed myeloid cells were also observed in western diet-trained myeloid cells, including type I IFN response genes and the IL-6 pathway ( Christ et al, 2018 ). Metabolic signaling has also been shown to be an important regulator of inflammatory memory responses in primed myeloid cells, resulting in a sensitized state with a lower threshold for activation, leading to an exaggerated inflammatory response ( Crişan et al, 2017 ; Keane et al, 2021 ; Ullevig et al, 2012 ).…”

Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas

“…Recently it has been shown that the mechanistic target of rapamycin (mTOR) signaling pathway is a powerful regulator of the microglial inflammatory response, including LPS-induced Il1b expression. 36 Therefore, mTOR kinase activation was examined in siCtrl and si Ezh2 BV2 cells following coculture with H3-K27M SF8628 DIPG cells or wild-type H3 SF188 pHGG cells. Indeed, we found increased phosphorylation, of one of the main substrates of mTOR, S6 ribosomal protein, suggesting an activation of the mTOR pathway in si Ezh2 BV2 cells consistent with an increased pro-inflammatory phenotype 36 ( Figure 4H ).…”

“… 36 Therefore, mTOR kinase activation was examined in siCtrl and si Ezh2 BV2 cells following coculture with H3-K27M SF8628 DIPG cells or wild-type H3 SF188 pHGG cells. Indeed, we found increased phosphorylation, of one of the main substrates of mTOR, S6 ribosomal protein, suggesting an activation of the mTOR pathway in si Ezh2 BV2 cells consistent with an increased pro-inflammatory phenotype 36 ( Figure 4H ). Overall, these observations suggested that si Ezh2 microglia may exhibit anti-tumoral properties and therefore we decided to investigate this possibility using several functional assays to measure anti-tumoral capabilities.…”

Senescent Microglia: The Key to the Ageing Brain?

“…Aged microglia have also been described as ‘primed’ [ 62 , 70 , 71 ], whereby the threshold for the microglia to be triggered to an activated state is substantially lower, and this has been suggested to be under the control of mTOR-dependent translation [ 72 ]. Interestingly, mTOR signalling has been reported to be impaired by TREM2 deficiency [ 69 ].…”