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

• Published in: Science advances 2019-06, Vol.5 (6), p.eaaw0254-eaaw0254
• Main Authors: Hari, Priya, Millar, Fraser R, Tarrats, Nuria, Birch, Jodie, Quintanilla, Andrea, Rink, Curtis J, Fernández-Duran, Irene, Muir, Morwenna, Finch, Andrew J, Brunton, Valerie G, Passos, João F, Morton, Jennifer P, Boulter, Luke, Acosta, Juan Carlos
• Format: Article
• Language: English
• Subjects: Alarmins - metabolism; Animals; Cancer; Cell Biology; Cellular Senescence - drug effects; Fibroblasts - cytology; Fibroblasts - metabolism; Humans; Immunity, Innate; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Nucleotidyltransferases - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; ras Proteins - genetics; ras Proteins - metabolism; RNA Interference; RNA, Small Interfering - metabolism; SciAdv r-articles; Serum Amyloid A Protein - genetics; Serum Amyloid A Protein - metabolism; Signal Transduction; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Toll-Like Receptor 10 - antagonists & inhibitors; Toll-Like Receptor 10 - genetics; Toll-Like Receptor 10 - metabolism; Toll-Like Receptor 2 - antagonists & inhibitors; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaw0254

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.