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.