Department of Psychology & Neuroscience, Baylor University, Waco, TX, 76798, United States; Department of Symptom Research, Laboratory of Neuroimmunology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States.
Department of Symptom Research, Laboratory of Neuroimmunology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States.
Psychoneuroendocrinology. 2020 Dec;122:104874. doi: 10.1016/j.psyneuen.2020.104874. Epub 2020 Sep 16.
Cancer-related fatigue at the time of tumor diagnosis is commonly attributed to inflammation associated with the disease process. However, we have previously demonstrated that running wheel deficits occur well before increased expression of proinflammatory cytokines in the liver and brain in a murine model of human papilloma virus-related head and neck cancer (mEER). Further, we have demonstrated that genetic deletion of type I interleukin-1 receptor and MyD88 has no effect. In the current investigation we sought to test the generality of this finding by assessing whether there is a role for toll-like receptor (TLR) 4-dependent inflammation in the fatigue-like behavior observed in mice with Lewis Lung Carcinoma (LLC) or mEER tumors. Genetic deletion of TLR4 attenuated tumor-induced elevations in liver pro-inflammatory cytokine expression in both models. However, it only abrogated wheel running deficits in LLC tumor bearing mice. To determine whether TLR4 signaling in the LLC model involves innate immune cells, mice were treated with the colony stimulating factor (CSF)-1 receptor antagonist PLX-5622 before and throughout tumor development to deplete microglia and peripheral macrophages. Administration of PLX-5622 had no protective effect on wheel running deficits in either mEER or LLC tumor models despite effective depletion of microglia and a down regulation of peripheral proinflammatory cytokine expression. These results indicate that the TLR4 signaling that mediates fatigue-like behavior in LLC mice is not dependent upon microglial or peripheral macrophage activation. Based on the literature and our data demonstrating attenuation of ubiquitin proteasome pathway activation in the gastrocnemius muscle of Tlr4 mice implanted with LLC cells, we interpret our current findings as indication that skeletal muscle TLR4 signaling may be involved. These results are important in that they add to the evidence that tumor-induced fatigue develops independently from classical neuroinflammation.
肿瘤诊断时的癌症相关疲劳通常归因于与疾病过程相关的炎症。然而，我们之前已经证明，在人类乳头瘤病毒相关头颈部癌症（mEER）的小鼠模型中，肝脏和大脑中促炎细胞因子表达增加之前，跑步轮缺陷就已经出现。此外，我们还证明了 I 型白细胞介素 1 受体和 MyD88 的基因缺失没有影响。在当前的研究中，我们通过评估 Lewis 肺癌（LLC）或 mEER 肿瘤小鼠中观察到的疲劳样行为是否与 Toll 样受体（TLR）4 依赖性炎症有关，来测试这一发现的普遍性。TLR4 基因缺失减弱了两种模型中肝脏促炎细胞因子表达的肿瘤诱导升高。然而，它仅消除了 LLC 荷瘤小鼠的跑步轮缺陷。为了确定 LLC 模型中 TLR4 信号是否涉及固有免疫细胞，在肿瘤发生前后用集落刺激因子（CSF）-1 受体拮抗剂 PLX-5622 处理小鼠，以耗尽小胶质细胞和外周巨噬细胞。尽管有效耗尽小胶质细胞并下调外周促炎细胞因子表达，但 PLX-5622 给药对 mEER 或 LLC 肿瘤模型中的跑步轮缺陷均无保护作用。这些结果表明，介导 LLC 小鼠疲劳样行为的 TLR4 信号不依赖于小胶质细胞或外周巨噬细胞的激活。基于文献和我们的数据表明，在植入 LLC 细胞的 Tlr4 小鼠的比目鱼肌中，泛素蛋白酶体途径的激活被减弱，我们将当前的发现解释为表明骨骼肌 TLR4 信号可能参与其中。这些结果很重要，因为它们增加了肿瘤诱导的疲劳独立于经典神经炎症发展的证据。
