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

Priya Hari; Fraser R. Millar; Nuria Tarrats; Jodie Birch; Andrea Quintanilla; Curtis J. Rink; Irene Fernández-Duran; Morwenna Muir; Andrew J. Finch; Valerie G. Brunton; João F. Passos; Jennifer P. Morton; Luke Boulter; Juan Carlos Acosta

doi:10.1126/sciadv.aaw0254

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

Priya Hari, Fraser R. Millar, Nuria Tarrats, Jodie Birch, Andrea Quintanilla, Curtis J. Rink, Irene Fernández-Duran, Morwenna Muir, Andrew J. Finch, Valerie G. Brunton, João F. Passos, Jennifer P. Morton, Luke Boulter, Juan Carlos Acosta

Physiology & Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

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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^CIP1, p16^INK4a, and p15^INK4b 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.

Original language	English (US)
Article number	aaw0254
Journal	Science Advances
Volume	5
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.aaw0254
State	Published - Jun 5 2019

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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., & Acosta, J. C. (2019). The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Science Advances, 5(6), Article aaw0254. https://doi.org/10.1126/sciadv.aaw0254

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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-p21CIP1, p16INK4a, and p15INK4b 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.",

author = "Priya Hari and Millar, {Fraser R.} and Nuria Tarrats and Jodie Birch and Andrea Quintanilla and Rink, {Curtis J.} and Irene Fern{\'a}ndez-Duran and Morwenna Muir and Finch, {Andrew J.} and Brunton, {Valerie G.} and Passos, {Jo{\~a}o F.} and Morton, {Jennifer P.} and Luke Boulter and Acosta, {Juan Carlos}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

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AU - Hari, Priya

AU - Millar, Fraser R.

AU - Tarrats, Nuria

AU - Birch, Jodie

AU - Quintanilla, Andrea

AU - Rink, Curtis J.

AU - Fernández-Duran, Irene

AU - Muir, Morwenna

AU - Finch, Andrew J.

AU - Brunton, Valerie G.

AU - Passos, João F.

AU - Morton, Jennifer P.

AU - Boulter, Luke

AU - Acosta, Juan Carlos

N1 - Publisher Copyright: © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2019/6/5

Y1 - 2019/6/5

N2 - 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-p21CIP1, p16INK4a, and p15INK4b 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.

AB - 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-p21CIP1, p16INK4a, and p15INK4b 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.

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

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