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

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Abstract / Description of output

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
Article number	eaaw0254
Number of pages	14
Journal	Science Advances
Volume	5
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.aaw0254
Publication status	Published - 5 Jun 2019

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10.1126/sciadv.aaw0254

The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory pheotype
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1 Finished
1 Active

The Edinburgh Clinical Academic Track (ECAT)-Plus Programme
Whyte, M.
1/08/17 → 31/07/25
Project: Research
Characterization of the Senescence Associated Extracellular Matrix (SA-ECM) and its role in cancer progression
Acosta, J.
UK-based charities
1/12/13 → 30/09/21
Project: Research

Luke Boulter
- Deanery of Molecular, Genetic and Population Health Sciences - Reader
- MRC Human Genetics Unit
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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 eaaw0254. https://doi.org/10.1126/sciadv.aaw0254

@article{b3406e9456004b51b3c6d806d788e995,

title = "The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype",

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}",

year = "2019",

month = jun,

day = "5",

doi = "10.1126/sciadv.aaw0254",

language = "English",

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T1 - The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

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

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.

U2 - 10.1126/sciadv.aaw0254

DO - 10.1126/sciadv.aaw0254

M3 - Article

SN - 2375-2548

VL - 5

JO - Science Advances

JF - Science Advances

IS - 6

M1 - eaaw0254

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

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Projects

The Edinburgh Clinical Academic Track (ECAT)-Plus Programme

Characterization of the Senescence Associated Extracellular Matrix (SA-ECM) and its role in cancer progression

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Luke Boulter

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