Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA; Medical Scientist Training Program, Oregon Health & Science University, Portland, OR, USA.
Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, USA.
Brain Behav Immun. 2018 Oct;73:364-374. doi: 10.1016/j.bbi.2018.05.021. Epub 2018 May 28.
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.
下丘脑炎症是急性疾病行为和恶病质的一个关键组成部分，但中枢神经系统中炎症信号的机制仍不清楚。我们实验室和其他实验室的先前工作表明，虽然 MyD88 是疾病行为的一个重要炎症信号通路，但 MyD88 敲除 (MyD88KO) 小鼠在炎症刺激挑战后仍会出现疾病行为。我们发现，在全身给予脂多糖 (LPS) 挑战后，MyD88KO 小鼠在下丘脑中几种细胞因子和趋化因子基因的表达升高。因此，我们评估了另一种炎症信号通路 TRIF 在急性炎症 (LPS 挑战) 和慢性炎症状态 (癌症恶病质) 中的作用。TRIFKO 小鼠在腹腔内 (腹腔内，IP) 或中枢 (脑室内，ICV) LPS 挑战以及胰腺癌恶病质模型中抵抗厌食和体重减轻。与 WT 小鼠相比，TRIFKO 小鼠在 IP LPS 治疗后下丘脑的 Il6、Ccl2、Ccl5、Cxcl1、Cxcl2 和 Cxcl10 上调减弱，ICV LPS 治疗后小胶质细胞激活和中性粒细胞浸润到大脑减弱。最后，我们发现 TRIF 是下丘脑 Ccl2 上调和胰腺癌细胞中代谢基因 Mafbx、Murf1 和 Foxo1 诱导所必需的。总之，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，为这些疾病提供了一个新的治疗靶点。
