Role of Macrophage-Mediated Toll-like receptor 4–Interleukin-1R Signaling in Ectopic Tongue Pain Associated With Tooth Pulp Inflammation

Abstract Background Ectopic orofacial pain is frequently caused by tooth pulp inflammation. However, the detailed mechanism underlying such pain remains poorly understood.Methods To better understand this phenomenon, ectopic pain mechanism was studied in a rat model of mandibular first molar tooth pulp exposure (M1-TPE).Results One day after M1-TPE, obvious pulpal inflammation was observed in M1 pulp. The head withdrawal threshold to mechanical and heat stimulation of the tongue was significantly reduced in M1-TPE rats on day 1 after TPE. In addition, the production of interleukin-1β (IL-1β) in activated macrophages and expression levels of Toll-like receptors (TLRs) and IL-1 type I receptor (IL-1RΙ) were significantly increased in the trigeminal ganglion (TG) neurons innervating the tongue following M1-TPE. Injection of the selective macrophage depletion compound liposomal clodronate Clophosome-A into the TG significantly suppressed tongue hypersensitivity; however, expression levels of TLR4 and IL-1RΙ in TG neurons innervating the tongue were not significantly altered. Injection of lipopolysaccharide from Rhodobacter sphaeroides, a TLR4 antagonist, into the TG following TPE significantly suppressed tongue hypersensitivity and reduced IL-1RΙ expression in TG neurons innervating the tongue. Moreover, an intra-TG injection of recombinant heat shock protein 70, a selective TLR4 agonist, significantly promoted the development of tongue-hypersensitivity and increased the production of IL-1RI in TG neurons innervating the tongue in naive rats. Furthermore, an intra-TG injection of recombinant IL-1β led to the development of tongue hypersensitivity in naive rats and enhanced the expression of transient receptor potential vanilloid 1 in the TG neurons innervating the tongue.Conclusions The present findings suggest that the neuron-macrophage interaction mediated by TLR4 and IL-1RI activation in TG neurons affects the pathogenesis of abnormal tongue pain following tooth pulp inflammation via TLR4-ILR and TRPV1 signaling in the TG.