TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice.
TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice.
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DOI：
10.7554/elife.03464
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发表时间：
2014-12-02
期刊：
影响因子：
7.7
通讯作者：
Silke J
中科院分区：
文献类型：
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作者：
Rickard JA;Anderton H;Etemadi N;Nachbur U;Darding M;Peltzer N;Lalaoui N;Lawlor KE;Vanyai H;Hall C;Bankovacki A;Gangoda L;Wong WW;Corbin J;Huang C;Mocarski ES;Murphy JM;Alexander WS;Voss AK;Vaux DL;Kaiser WJ;Walczak H;Silke J
SHARPIN调节免疫信号传导，并有助于充分转录活性和预防体外响应TNF的细胞死亡。失活的小鼠Sharpin cpdm突变导致TNF依赖性多器官炎症，其特征在于皮炎、肝脏炎症、脾肿大和派伊尔集合淋巴结的丧失。已经提出TNF依赖性细胞死亡导致炎症表型，并且与此一致，我们显示Tnfr 1而不是Tnfr 2缺陷抑制表型（并且它比Il 1 r1损失更有效）。TNFR 1诱导的细胞凋亡可以通过caspase-8和BID进行，但是这些参与者的减少或丢失通常不能抑制炎症，尽管Casp 8杂合性显著延迟皮炎。Ripk 3或Mlkl缺陷部分改善了多器官表型，而Ripk 3缺失和Casp 8杂合性的组合几乎完全抑制了它，甚至恢复了派伊尔集合淋巴结。出乎意料的是，Sharpin、Ripk 3和Casp 8三重缺陷导致围产期死亡。这些结果为SHARPIN的发育重要性提供了意想不到的见解。DOI：http://dx.doi.org/10.7554/eLife.03464.001在对受伤或感染的反应中，当免疫系统试图修复损伤和/或破坏进入体内的任何微生物或毒素时，身体的某些部位可能会发炎。在单个细胞的水平上，炎症可能涉及细胞以两种方式之一被编程为死亡：凋亡和坏死性凋亡。细胞凋亡是一个高度受控的过程，在此过程中，细胞的内容物被安全地破坏，以防止对周围细胞的损害。另一方面，坏死是不受控制的：细胞破裂并将其内容物释放到周围环境中。炎症是由一种名为TNFR 1的蛋白质激活的，TNFR 1由一种包括SHARPIN蛋白质的复合物控制。缺乏SHARPIN蛋白的小鼠即使没有受伤或感染，也会在皮肤和内脏器官上产生炎症。然而，目前尚不清楚SHARPIN如何控制TNFR 1来预防炎症。Rickard等人和Kumari等人现在已经独立地详细研究了这一过程。Rickard等人将缺乏SHARPIN的小鼠与缺乏其他参与炎症和细胞死亡的蛋白质的小鼠杂交。实验表明，细胞凋亡是皮肤炎症中细胞死亡的主要形式，而坏死性凋亡在内脏器官炎症中的作用更大。缺乏凋亡和坏死性细胞死亡途径的小鼠可以相对正常地发育，但如果它们也缺乏SHARPIN，它们在出生后不久就会死亡。对这些小鼠的实验可以帮助我们了解SHARPIN是如何工作的。DOI：http://dx.doi.org/10.7554/eLife.03464.002网站
SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN. DOI: http://dx.doi.org/10.7554/eLife.03464.001 In response to an injury or infection, areas of the body can become inflamed as the immune system attempts to repair the damage and/or destroy any microbes or toxins that have entered the body. At the level of individual cells inflammation can involve cells being programmed to die in one of two ways: apoptosis and necroptosis. Apoptosis is a highly controlled process during which the contents of the cell are safely destroyed in order to prevent damage to surrounding cells. Necroptosis, on the other hand, is not controlled: the cell bursts and releases its contents into the surroundings. Inflammation is activated by a protein called TNFR1, which is controlled by a complex that includes a protein called SHARPIN. Mice that lack the SHARPIN protein develop inflammation on the skin and internal organs, even in the absence of injury or infection. However, it is not clear how SHARPIN controls TNFR1 to prevent inflammation. Rickard et al. and, independently Kumari et al. have now studied this process in detail. Rickard et al. cross bred mice that lack SHARPIN with mice lacking other proteins involved in inflammation and cell death. The experiments show that apoptosis is the main form of cell death in skin inflammation, but necroptosis has a bigger role in the inflammation of internal organs. Mice that lack both the apoptotic and necroptotic cell-death pathways can develop relatively normally, but they die shortly after birth if they also lack SHARPIN. Experiments on these mice could help us to understand how SHARPIN works. DOI: http://dx.doi.org/10.7554/eLife.03464.002