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SIRT1 regulates macrophage self-renewal

Item Type:Article
Title:SIRT1 regulates macrophage self-renewal
Creators Name:Imperatore, F. and Maurizio, J. and Vargas Aguilar, S. and Busch, C.J. and Favret, J. and Kowenz-Leutz, E. and Cathou, W. and Gentek, R. and Perrin, P. and Leutz, A. and Berruyer, C. and Sieweke, M.H.
Abstract:Mature differentiated macrophages can self-maintain by local proliferation in tissues and can be extensively expanded in culture under specific conditions, but the mechanisms of this phenomenon remain only partially defined. Here, we show that SIRT1, an evolutionary conserved regulator of life span, positively affects macrophage self-renewal ability in vitro and in vivo Overexpression of SIRT1 during bone marrow-derived macrophage differentiation increased their proliferative capacity. Conversely, decrease of SIRT1 expression by shRNA inactivation, CRISPR/Cas9 mediated deletion and pharmacological inhibition restricted macrophage self-renewal in culture. Furthermore, pharmacological SIRT1 inhibition in vivo reduced steady state and cytokine-induced proliferation of alveolar and peritoneal macrophages. Mechanistically, SIRT1 inhibition negatively regulated G1/S transition, cell cycle progression and a network of self-renewal genes. This included inhibition of E2F1 and Myc and concomitant activation of FoxO1, SIRT1 targets mediating cell cycle progression and stress response, respectively. Our findings indicate that SIRT1 is a key regulator of macrophage self-renewal that integrates cell cycle and longevity pathways. This suggests that macrophage self-renewal might be a relevant parameter of ageing.
Keywords:Cell Cycle Regulation, Macrophage, Replicative Life Span, Selfrenewal, Sirtuins, Animals, Mice
Source:EMBO Journal
ISSN:0261-4189
Publisher:EMBO Press (U.S.A.)
Volume:36
Number:16
Page Range:2353-2372
Date:15 August 2017
Official Publication:https://doi.org/10.15252/embj.201695737
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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