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

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

doi:10.1126/sciadv.aaw0254

Cited by 105 publications

(94 citation statements)

References 55 publications

(86 reference statements)

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“…3A). Among them, FOXA1, PLAT, CD44, FGF5, DIO2 and other genes are upregulated, whereas PLCB1, SETBP1, EHD3, ZNF423, PHGDH and other genes are downregulated in multiple senescence systems(Chan et al, 2019; Cho et al, 2019; Galanos et al, 2016; Hari et al, 2019; Hernandez-Segura et al, 2017; Komseli et al, 2018; Lau, Porciuncula, Yu, Iwakura, & David, 2019; Leveque et al, 2019; Q. Li et al, 2013; Limbad et al, 2020; Lowe & Raj, 2014; Nagano et al, 2016; Pan et al, 2019; Pantazi et al, 2019; Suwan et al, 2009; Wu, Pepowski, Takahashi, & Kron, 2019; Zhou et al, 2010), as are consistent with our results.…”

Section: Resultssupporting

confidence: 92%

ATF3 drives senescence by reconstructing accessible chromatin profiles

Zhang

Guan

et al. 2020

Preprint

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Chromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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Section: Resultssupporting

confidence: 92%

ATF3 drives senescence by reconstructing accessible chromatin profiles

Zhang

Guan

et al. 2020

Preprint

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“…A recent study shows the involvement of Toll-like receptor 2 (TLR2) via the TP53, p16 and p15 pathways, thereby inducing cell cycle arrest and induction of acute-phase serum amyloids, which are part of damage-associated molecular patterns (DAMP). DAMPs in turn signal through pattern recognition receptors of the innate immune system such as TLR2, thereby controlling the SASP and reinforcing cell cycle arrest during senescence [26].…”

Section: Introductionmentioning

confidence: 99%

Functional heterogeneity in senescence

Kirschner

Rattanavirotkul

Quince

et al. 2020

Biochemical Society Transactions

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Senescence is a tumour suppressor mechanism which is cell-intrinsically activated in the context of cellular stress. Senescence can further be propagated to neighbouring cells, a process called secondary senescence induction. Secondary senescence was initially shown as a paracrine response to the secretion of cytokines from primary senescent cells. More recently, juxtacrine Notch signalling has been implicated in mediating secondary senescence induction. Primary and secondary senescent induction results in distinct transcriptional outcomes. In addition, cell type and the stimulus in which senescence is induced can lead to variations in the phenotype of the senescence response. It is unclear whether heterogeneous senescent end-points are associated with distinct cellular function in situ, presenting functional heterogeneity. Thus, understanding senescence heterogeneity could prove to be important when devising ways of targeting senescent cells by senolytics, senostatics or senogenics. In this review, we discuss a role for functional heterogeneity in senescence in tissue- and cell-type specific manners, highlighting potential differences in senescence outcomes of primary and secondary senescence.

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“…Herein, we demonstrated that low activity of TLR2 and TLR5 regulated SASP secretion in small cells from MSCs. Studies have already reported that TLR2 and TLR5 are important factors in the regulation of cellular senescence [ 45 , 46 ]. According to Hari et al, innate immune sensing of senescence-related damage-associated molecular patterns (DAMPs) by TLR2 mediated the SASP and improved the cell cycle arrest program in oncogene induce senescence (OIS) [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling

Kwon

Kim

et al. 2021

Cells

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In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

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

Cited by 105 publications

References 55 publications

ATF3 drives senescence by reconstructing accessible chromatin profiles

ATF3 drives senescence by reconstructing accessible chromatin profiles

Functional heterogeneity in senescence

Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling

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