and TLR receptors that respond to many immune signals including cytokines and endogenous TLR agonists, such as HMGB1, a ubiquitous protein and TLR receptor agonist [42,47,48]. Microglia are uniquely sensitive to the brain environment and are thought to initiate neuroinflammatory responses [6]. This is consistent with our finding of increasing morphological activation of microglia coinciding with induction of brain TNFα, IL-1β, IL-6, and MCP-1 mRNA and blood protein levels of these cytokines and chemokines (Figure 13). However, endothelial cells in brain form the blood–brain barrier and both transport and increase synthesis and secretion of cytokines into brain [49]. Our findings are consistent with increases in blood proinflammatory cytokines contributing to activation of brain microglia, endothelial cells and neuroinflammatory gene induction in multiple types of brain cells (See Figure 13).
