The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

Hari, P. et al. (2019) The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Science Advances, 5(6), eaaw0254. (doi: 10.1126/sciadv.aaw0254) (PMID:31183403) (PMCID:PMC6551188)

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Abstract

Cellular senescence is a stress response program characterized by a robust cell cycle arrest and the induction of a proinflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that, during oncogene-induced senescence (OIS), the Toll-like receptor 2 (TLR2) and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumor suppressors p53-p21 , p16 , and p15 and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAAs) that, in turn, function as the damage-associated molecular patterns (DAMPs) signaling through TLR2 in OIS. Last, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAAs expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK (C47559/A16243, Training and Career Development Board–Career Development Fellowship), University of Edinburgh (Chancellor’s Fellowship), and the Wellcome Trust-ISSF. P.H., I.F.-D., and N.T. were funded by the University of Edinburgh Chancellor’s Fellowship. J.F.P. and J.B. were funded by BBSRC (grant no. BB/K017314/1). F.R.M. is funded by a Wellcome Trust Clinical Research Fellowship through the Edinburgh Clinical Academic Track (ECAT) (203913/Z/16/Z). J.P.M. and C.J.R. are funded by CRUK (A20409 and A25142).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rink, Curtis and Morton, Professor Jen
Authors: Hari, P., Millar, F. R., Tarrats, N., Birch, J., Quintanilla, A., Rink, C. J., Fernández-Duran, I., Muir, M., Finch, A. J., Brunton, V. G., Passos, J. F., Morton, J. P., Boulter, L., and Acosta, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Science Advances 5(6):eaaw0254
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research