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TRAIL Receptors Serve as Stress-Associated Molecular Patterns to Promote ER-Stress-Induced Inflammation.
Developmental Cell ( IF 10.7 ) Pub Date : 2020-02-12 , DOI: 10.1016/j.devcel.2020.01.031 Graeme P Sullivan 1 , Hazel O'Connor 1 , Conor M Henry 1 , Pavel Davidovich 1 , Danielle M Clancy 1 , Matthew L Albert 2 , Sean P Cullen 2 , Seamus J Martin 1
Developmental Cell ( IF 10.7 ) Pub Date : 2020-02-12 , DOI: 10.1016/j.devcel.2020.01.031 Graeme P Sullivan 1 , Hazel O'Connor 1 , Conor M Henry 1 , Pavel Davidovich 1 , Danielle M Clancy 1 , Matthew L Albert 2 , Sean P Cullen 2 , Seamus J Martin 1
Affiliation
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Inflammation triggered by infection or cellular necrosis is initiated by a battery of pattern-recognition receptors, such as Toll-like receptors or IL-1 family receptors. Diverse forms of cell stress, such as ER stress or mitochondrial stress, can also promote inflammatory responses that contribute to the chronic inflammation observed in cancer, obesity, and other conditions. However, the molecular mechanisms of cell-stress-induced inflammation are poorly understood. Here, we show that ER stress initiated NF-κB activation and inflammation through transcriptional upregulation and ligand-independent activation of TRAIL receptors. ER-stress-induced TRAIL receptor activation resulted in caspase-8/FADD/RIPK1-dependent NF-κB activation and inflammatory cytokine production. Silencing or deletion of TRAIL receptors, or their downstream effectors caspase-8, FADD, or RIPK1, suppressed ER-stress-induced inflammation. Furthermore, chemotherapeutic stress-induced inflammatory responses were blunted in DR5/TRAIL-R null animals. We propose that, upon ER stress, TRAIL receptors serve as "stress-associated molecular patterns (SAMPs)" coupling ER stress to NF-κB-dependent inflammation.
中文翻译：
TRAIL受体作为应激相关的分子模式，以促进ER应力诱导的炎症。
感染或细胞坏死触发的炎症由一系列模式识别受体（例如Toll样受体或IL-1家族受体）引发。多种形式的细胞应激（例如ER应激或线粒体应激）也可以促进炎症反应，从而导致在癌症，肥胖症和其他疾病中观察到的慢性炎症。但是，人们对细胞应激诱导的炎症的分子机制了解甚少。在这里，我们显示ER应激通过转录上调和TRAIL受体的配体非依赖性激活来启动NF-κB激活和炎症。内质网应激诱导的TRAIL受体激活导致caspase-8 / FADD / RIPK1依赖性NF-κB激活和炎性细胞因子的产生。沉默或删除TRAIL受体或其下游效应子caspase-8，FADD或RIPK1可抑制内质网应激诱导的炎症。此外，在DR5 / TRAIL-R无效动物中，化疗应激诱导的炎症反应减弱。我们建议，在ER应激时，TRAIL受体充当“应激相关分子模式（SAMPs）”，将ER应激耦合至NF-κB依赖性炎症。
更新日期：2020-02-27
中文翻译：
TRAIL受体作为应激相关的分子模式，以促进ER应力诱导的炎症。
感染或细胞坏死触发的炎症由一系列模式识别受体（例如Toll样受体或IL-1家族受体）引发。多种形式的细胞应激（例如ER应激或线粒体应激）也可以促进炎症反应，从而导致在癌症，肥胖症和其他疾病中观察到的慢性炎症。但是，人们对细胞应激诱导的炎症的分子机制了解甚少。在这里，我们显示ER应激通过转录上调和TRAIL受体的配体非依赖性激活来启动NF-κB激活和炎症。内质网应激诱导的TRAIL受体激活导致caspase-8 / FADD / RIPK1依赖性NF-κB激活和炎性细胞因子的产生。沉默或删除TRAIL受体或其下游效应子caspase-8，FADD或RIPK1可抑制内质网应激诱导的炎症。此外，在DR5 / TRAIL-R无效动物中，化疗应激诱导的炎症反应减弱。我们建议，在ER应激时，TRAIL受体充当“应激相关分子模式（SAMPs）”，将ER应激耦合至NF-κB依赖性炎症。
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