Endocannabinoid regulation of neuroinflammatory responses following acute systemic viral (TLR3) and bacterial (TLR4) infection
Henry, Rebecca Jane
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Toll like receptors (TLRs) are key players in host defence, homeostasis and response to injury. However, uncontrolled and aberrant TLR activation has been proposed to trigger the onset of certain neurodegenerative disorders and elicit detrimental effects on the progression and outcome of established disease. There is now accumulating evidence demonstrating potent immunoregulatory effects of the endogenous cannabinoid (endocannabinoid) system on neuroinflammatory processes and suggesting that this system may represent an important therapeutic target in the treatment of neuroinflammatory and neurodegenerative disorders. The main objective of the work presented in this thesis was to investigate the role of the brain's endocannabinoid system in the modulation of acute neuroinflammatory responses, induced following systemic viral (TLR3) and bacterial (TLR4) infection. The enhancement of endocannabinoid tone was achieved by inhibiting the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), that preferentially catabolise the primary endocannabinoids in the brain, namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The data presented herein demonstrate through a series of experiments that the inhibition of FAAH and enhancement of FAAH substrate levels directly within the brain, and not via peripheral modulatory mechanisms, robustly attenuates TLR3-induced neuroinflammatory processes. These effects were shown to be mediated by FAAH substrate-mediated activation of cannabinoid1 (CB1) receptors and the peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma within the brain. In comparison, enhancing endogenous 2-AG tone, through MAGL inhibition, was associated with an augmentation of TLR3-induced expression of both interferon (IFN) - and NF-kappaB-inducible inflammatory genes within the hippocampus. Thus, these findings indicate differential effects of FAAH substrates (anti-inflammatory) vs. 2-AG (pro-inflammatory) on TLR3-induced neuroinflammatory responses in an in vivo model system. In addition, work in this thesis also demonstrated for the first time that enhancement of FAAH substrates directly within the brain, is associated with potent anti-inflammatory effects on TLR4-induced neuroinflammation. Such anti-inflammatory effects were independent of brain cannabinoid (CB1, CB2 and G-protein coupled receptor (GPR) 55)) receptors or PPARs (PPAR-alpha/gamma), but rather were shown to be mediated, at least in part, via activation of TRPV1 directly within the brain. In conclusion, the data presented in this thesis extend the body of knowledge regarding endocannabinoid modulation of neuroinflammatory responses to acute bacterial (TLR4) and viral (TLR3) infection, and may inform the development of novel therapeutics for acute and chronic neuroinflammatory disorders.