Protective roles for caspase-8 and cFLIP in adult homeostasis.
Protective roles for caspase-8 and cFLIP in adult homeostasis.
复制标题
DOI：
10.1016/j.celrep.2013.08.045
复制
发表时间：
2013-10-31
期刊：
影响因子：
8.8
通讯作者：
Green DR
中科院分区：
文献类型：
--
作者：
Weinlich R;Oberst A;Dillon CP;Janke LJ;Milasta S;Lukens JR;Rodriguez DA;Gurung P;Savage C;Kanneganti TD;Green DR
Caspase-8或cFLIP缺陷导致小鼠胚胎死亡，原因是内皮组织缺陷。Caspase-8−/−，RIPK 3 −/−，但不是cFLIP−/−，RIPK 3 −/−，双敲除动物发育正常，表明caspase-8拮抗RIPK 3在发育过程中的致死作用。在这里，我们表明，急性缺失的caspase-8在肠道的成年小鼠诱导肠上皮细胞死亡，破坏组织稳态和炎症，导致败血症和死亡。同样，皮肤病灶区域中半胱天冬酶-8的急性缺失诱导局部角质形成细胞死亡、组织破坏和炎症。引人注目的是，RIPK 3消融挽救了两种表型。皮肤中cFLIP的急性丢失产生类似的表型，然而，RIPK 3消融不能挽救这种表型。TNF中和可防止caspase-8或cFLIP的急性丢失。这些结果表明，caspase-8介导的抑制RIPK 3诱导的死亡不仅需要在发展过程中，但也为成人稳态。此外，RIPK 3依赖性炎症与皮肤表型无关。
Caspase-8 or cFLIP deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8−/−, RIPK3−/−, but not cFLIP−/−, RIPK3−/−, double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. Acute loss of cFLIP in the skin produces a similar phenotype, which, however, is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development, but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.
登录
查看更多内容
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR
影响因子：
4.4
作者：
Beisner, DR;Ch'en, IL;Hedrick, SM
通讯作者：
Hedrick, SM
DOI：
10.1111/j.1749-6632.2010.05742.x
发表时间：
2010-01-01
期刊：
CLEARANCE OF DYING CELLS IN HEALTHY AND DISEASED IMMUNE SYSTEMS
影响因子：
--
作者：
Wallach, David;Kang, Tae-Bong;Kovalenko, Andrew
通讯作者：
Kovalenko, Andrew