Endocannabinoid modulation of TLR3-induced neuroinflammation

Toll-like receptors (TLRs) play a key role in the recognition and activation of the innate immune system in response to infection. However, aberrant TLR activation has been implicated in predisposing to, and exacerbating, the pathological processes underlying a number of neuroinflammatory disorders. Increasing evidence demonstrates that the endogenous cannabinoid (endocannabinoid) system has potent immunomodulatory effects and represents a potential therapeutic target for peripheral and central inflammatory disorders. Thus, the main objective of the work presented in this thesis was to investigate the role of the endocannabinoid system in the modulation of acute viral (TLR3)-induced peripheral and central inflammatory responses and potential sex differences in these responses. The data herein demonstrate for the first time that the acute phase inflammatory, endocrine and sickness responses to TLR3 activation exhibit minimal sex-related differences in male and female rats, indicating that data obtained in one sex in relation to acute viral TLR3 responses may pertain to both. Increasing levels of FAAH substrates, including the endocannabinoid AEA, attenuates the TLR3-induced inflammatory responses in the hypothalamus, but not in the spleen, of male and female rats. There was no effect of elevating levels of 2-AG on TLR3-induced inflammation. Further studies indicated that the suppressive effect of FAAH substrate elevation on TLR3-induced neuroinflammation was centrally mediated and associated with attenuation of the TLR3-induced fever response, reduced nociceptive responding and a reversal of TLR3-induced anxiety-like behaviour. Thus FAAH substrates attenuate TLR3-induced neuroinflammatory responses and associated changes in temperature, nociception and emotional (anxiety) behaviour. Further studies were conducted to determine if the effects of URB597 were due to increases in one or other of the FAAH substrates and the possible role of CB1/CB2 receptors in mediating the effects. The data demonstrated a partial role for CB1 receptors in the inhibitory effects of the FAAH inhibitor URB597 on TLR3-induced neuroinflammation and fever and a role for CB2 receptors in the attenuation of the TLR3-induced fever response. However, central administration of methanandamide or CB1 or CB2 receptor agonists did not attenuate TLR3-induced neuroinflammation or the fever response. The systemic administration of OEA attenuated the TLR3-induced neuroinflammatory response and fever while PEA attenuated TLR3-induced fever, but not the neuroinflammatory response. Taken together the data demonstrate that FAAH inhibition attenuates acute TLR3-induced responses in the brain, but not the periphery, and indicate a role for CB1/CB2 receptors and the FAAH substrate OEA, at least in part, in mediating these effects, however a role for alternative receptor targets cannot be ruled out. In conclusion, the data presented in this thesis have enhanced our knowledge of FAAH substrate modulation of neuroinflammation, sickness and behavioural responses following acute viral TLR3 activation, effects which may have important implications for dampening the neuroinflammatory response following viral infection and alleviating CNS disorders with a neuroinflammatory component.

Funder

Hardiman Postgraduate Scholarship

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

Collections

University of Galway Theses (PhD Theses)