Toll-like receptor expression and signalling in rat trigeminal neurons: Consequences for oral infection and mechanisms of orofacial pain.

Abstract

The activation of Toll-like receptors (TLRs), expressed by peripheral sensory neurons, represents an innate surveillance function of sensory neurons with important consequences for neuronal function. Despite recent advances, many properties of neuronal TLRs remain poorly understood, particularly within the trigeminal system. The main objectives of this thesis, therefore, were to better characterise the expression and functional consequences of activation of neuronal TLRs in the setting of orofacial pain. A detailed, quantitative description of TLR4, TLR2 and TLR7 expression within neurochemically- identified sub-populations of trigeminal ganglion (TG) sensory neurons suggests that these receptors are primarily expressed by nociceptor sub-populations. Acute activation of these TLRs, in TG neurons, induced an increased gene expression of the pro-inflammatory cytokines, TNF and IL-1 . In an attempt to identify further novel co-modulators of neuronal TLR activation, the expression of lysophosphatidylcholine acyltransferase (LPCAT) isoforms, a phospholipid remodelling enzyme that is known to mediate TLR4 activation in macrophages, are described within TG neurons. Under naïve conditions, LPCAT1 was expressed by a range of sensory neuron sub-types whereas LPCAT2 expression was confined to non-neuronal cells. Following nerve injury, the expression of LPCAT2 was induced in a small proportion of TG neurons in vitro whilst the expression of LPCAT1 remained unaltered. These results may support a role for LPCAT2 in neuronal TLR activation following a priming stimulus, such as nerve injury. Taken together, the results presented in this thesis support the hypothesis that trigeminal nociceptors can directly detect and respond to pathogenic challenge and tissue damage. The acute activation of TLRs, expressed by trigeminal nociceptors, results in the up-regulation of pro-inflammatory cytokines which are known to activate and sensitise neurons. The activation of neuronal TLRs may therefore contribute to the increased neuronal excitability and pain that accompanies common orofacial disorders.