Increased gut permeability and circulating cytokines are also thought to be responsible for alcohol-induced neuroimmune activation. Increased circulating cytokines in the periphery are associated with immune activation in the brain, which can persist for months after the peripheral immune response has subsided (Ferrier et al., 2006; Leclercq et al., 2012, 2014a). Peripherally-produced cytokines enter the brain via two mechanisms: (1) systemic circulation and (2) neural pathways (Banks, 2015). Pro-inflammatory molecules reach the CNS via BBB-deficient areas in the brain (e.g., circumventricular organs) by entering fenestrated capillaries of the BBB or through cytokine-specific trans-porters. Specifically, IL-1 s, IL-6, TNF-α, and IFN (interferon)-γ cross the BBB via saturable transport systems (Banks, 2005; Qin et al., 2009). The amount of blood-born cytokines that enter the CNS is comparable to other water-soluble compounds such as morphine (Banks, 2005). Cytokines also stimulate production of other cytokines, nitric oxide, and prostanoids on the abluminal membrane site of the brain (Banks and Erickson, 2010). The BBB expresses ΤLRs 1–4 and 6, suggesting that PAMPs like LPS may directly alter brain signaling (Nagyoszi et al., 2010). BBB permeability
