TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia.
TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia.
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DOI：
10.1016/j.bbi.2018.05.021
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Marks DL
中科院分区：
文献类型：
--
作者：
Burfeind KG;Zhu X;Levasseur PR;Michaelis KA;Norgard MA;Marks DL
下丘脑炎症是急性疾病行为和恶病质的关键组成部分，但中枢神经系统中炎症信号的机制尚不清楚。我们实验室和其他实验室以前的工作表明，虽然MyD88是疾病行为的重要炎症信号通路，但MyD88基因敲除(MyD88KO)小鼠在炎症刺激攻击后仍然经历疾病行为。我们发现，在系统脂多糖(LPS)攻击后，MyD88KO小鼠下丘脑中几种细胞因子和趋化因子基因的表达增加。因此，我们评估了额外的炎症信号通路TRIF在急性炎症(内毒素刺激)和慢性炎症状态(癌症恶病质)中的作用。TRIFKO小鼠在外周(腹膜内，IP)或中心(脑室内，ICV)内毒素攻击后，以及在胰腺癌恶病质模型中抵抗厌食和体重减轻。与WT小鼠相比，经ip内毒素治疗后，TRIFKO小鼠下丘脑IL6、CCL2、CCL5、CxCL1、CxCl2和CxCl10表达上调，脑室注射内毒素后小胶质细胞活化和中性粒细胞向脑内的浸润减少。最后，我们发现，在胰腺癌过程中，TRIF在下丘脑CCL2的上调和腓肠肌分解代谢基因Mafbx、MuRF1和Foxo1的诱导中是必需的。综上所述，我们的结果表明，TRIF是疾病行为和恶病质的重要炎症信号介质，并为这些疾病提供了一个新的治疗靶点。
Hypothalamic inflammation is a key component of acute sickness behavior and cachexia, yet mechanisms of inflammatory signaling in the central nervous system remain unclear. Previous work from our lab and others showed that while MyD88 is an important inflammatory signaling pathway for sickness behavior, MyD88 knockout (MyD88KO) mice still experience sickness behavior after inflammatory stimuli challenge. We found that after systemic lipopolysaccharide (LPS) challenge, MyD88KO mice showed elevated expression of several cytokine and chemokine genes in the hypothalamus. We therefore assessed the role of an additional inflammatory signaling pathway, TRIF, in acute inflammation (LPS challenge) and in a chronic inflammatory state (cancer cachexia). TRIFKO mice resisted anorexia and weight loss after peripheral (intraperitoneal, IP) or central (intracerebroventricular, ICV) LPS challenge and in a model of pancreatic cancer cachexia. Compared to WT mice, TRIFKO mice showed attenuated upregulation of Il6, Ccl2, Ccl5, Cxcl1, Cxcl2, and Cxcl10 in the hypothalamus after IP LPS treatment, as well as attenuated microglial activation and neutrophil infiltration into the brain after ICV LPS treatment. Lastly, we found that TRIF was required for Ccl2 upregulation in the hypothalamus and induction of the catabolic genes, Mafbx, Murf1, and Foxo1 in gastrocnemius during pancreatic cancer. In summary, our results show that TRIF is an important inflammatory signaling mediator of sickness behavior and cachexia and presents a novel therapeutic target for these conditions.
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DOI：
10.1084/jem.20111020
发表时间：
2011-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Braun TP;Zhu X;Szumowski M;Scott GD;Grossberg AJ;Levasseur PR;Graham K;Khan S;Damaraju S;Colmers WF;Baracos VE;Marks DL
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Marks DL
影响因子：
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DOI：
10.1523/jneurosci.2311-11.2011
发表时间：
2011-08-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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通讯作者：
Marks DL
DOI：
10.1523/jneurosci.0203-12.2012
发表时间：
2012-05-30
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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