Blockade of CCR2/5 signaling with CVC successfully limited the alcohol-induced infiltration of peripheral macrophages into the CNS. Previously, CVC was shown to be effective at limiting macrophage chemotaxis to the liver in a model of fibrosis [16]. While successful inhibition of peripheral immune cell infiltration is consistent with blockade of a chemokine receptor, blocking CCL2 signaling has additional advantages. In the CNS of CCL2 knockout mice, production of proinflammatory cytokines TNFα and IL-1β was significantly reduced after peripheral injection of bacterial endotoxin (lipopolysaccharide (LPS)) [28]. Interestingly, these proinflammatory cytokines were expressed even before peripheral cell infiltration occurred, suggesting that, at least in this model, neuroinflammatory gene expression preceded the response of the peripheral immune system. This has important implications for our present study, as it suggests that continued proinflammatory signaling within the CNS depends on chemoattraction of peripheral immune cells such as monocytes, which is inhibited by the small molecule CVC. Reducing inflammatory signaling in the CNS, which in the case of LPS precedes immune cell infiltration, may contribute to the reduced expression of chemokines. Cell-specific knockout of CCR2 (such
