Polyinosine-polycytidylic acid (poly I:C) is a synthetic double-stranded RNA that with endogenous co-agonists, such as high-mobility group box (HMGB) proteins, stimulates proinflammatory innate immune responses through TLR3 [8]. TLR3 receptors activate NF-κB in monocyte-microglia, astrocytes and other cells [7,9-14] and increase proinflammatory cytokine expression and neuroinflammation [15-18]. Although low levels of TLR3 are expressed in healthy human brains, multiple neurodegenerative diseases show increased expression of TLR3 receptors across brain regions [19]. Recent studies indicate that TLR receptors and endogenous agonist respond to cell stress, excessive glutamate excitation and/or other ‘danger’ signals [20,21]. For example, high-mobility group box 1 (HMGB1), an agonist at multiple TLR receptors and required for TLR3 activation [22], is released from cells by neurotransmitters including glutamate, proinflammatory cytokines and many other stimuli that amplify proinflammatory responses [3]. TLR3 may also play a role in neuroplasticity since TLR3-deficient mice have increased hippocampal neurogenesis and altered cognition [23]. These findings suggest that levels of brain HMGB1 and TLR receptors contribute to brain function and neuroinflammation.
