mTOR-dependent translation amplifies microglia priming in aging mice
Lily Keane, … , Michael T. Heneka, Melania Capasso
Lily Keane, … , Michael T. Heneka, Melania Capasso
Published October 27, 2020
Citation Information: J Clin Invest. 2021;131(1):e132727. https://doi.org/10.1172/JCI132727.
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Research Article Aging Inflammation

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 had upregulated mTOR complex 1 signaling controlling 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-κB–dependent upregulation of priming genes at the 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 that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration.

Authors

Lily Keane, Ignazio Antignano, Sean-Patrick Riechers, Raphael Zollinger, Anaelle A. Dumas, Nina Offermann, Maria E. Bernis, Jenny Russ, Frederike Graelmann, Patrick Neil McCormick, Julia Esser, Dario Tejera, Ai Nagano, Jun Wang, Claude Chelala, Yvonne Biederbick, Annett Halle, Paolo Salomoni, Michael T. Heneka, Melania Capasso

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Figure 5

mTORC1 exerts a stronger control over the inflammatory response through translation.

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mTORC1 exerts a stronger control over the inflammatory response through ...
(A) Microglia activation markers as assessed by flow cytometry of microglia from WT and Rheb-KO mice. Data are shown as MFI (n = 3). (B) Plasma levels of cytokines from young (2–6 months) and aged (15–20 months) WT and Rheb-KO mice, 4 hours after i.p. injection of 5 mg/kg LPS (n = 3). Cytokines were measured using a Legendplex assay system. (C) Results from open-field test of WT and Rheb-KO mice 6 hours after i.p. injection of 0.33 mg/mL LPS. Locomotor capabilities were assessed by the distance traveled by each mouse (number of squares it passes through) or by the number of times the mouse reared during the 5-minute test (n = 5–8). (D) TNF levels measured by ELISA from culture supernatants of acute brain slices from WT and Rheb-KO mice, after 6 hours of culture with 2 μg/mL LPS (n = 3). (E) Immunofluorescence staining of acute brain slices from WT and Rheb-KO mice treated with 2 μg/mL LPS for 6 hours. Green: TNF, red: IBA1 (microglia marker). Scale bar: 10 μm (objective 40×). (F) Relative fluorescence intensity (RFU) of proteins synthesized in WT and Rheb-KO BMDMs at the steady state and after stimulation with 100 ng/mL LPS (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; Student’s t test (A and C) and 2-way ANOVA (B, D, and F).