Toll-like receptor 7: Expression patterns within mammalian Trigeminal and Dorsal Root Ganglia and its selected facial innervation target, the tongue

Sara Kawamura


Toll-like receptors (TLRs) are known to be expressed in the mammalian nervous system where they play an important role in the hosts’ immune defence against bacterial and viral pathogens. Recent studies have looked into the expression of a wide range of TLRs in various neuronal sub-populations of the central and peripheral nervous systems. However, the co-expression of TLRs within the sub-populations of neurons as well as the expression of TLRs in the terminals of various innervation targets are yet to be understood. In this study, Immunohistochemistry was used to quantify the expression of TLR7 with known neurochemical markers in two sets of tissue samples from the cephalic nervous system of naïve rats, namely, the Trigeminal Ganglia (TG) and one of its innervation targets, the Tongue. The patterns of TLR7 expression within the TG were compared to that of the Dorsal Root Ganglia (DRG) of the same naïve rat, which showed no significant difference. Although very little co-localization was seen between TLR7 and its co-stained neurochemical markers, NF200 and IB4, more co-localization was seen with IB4 than with NF200. On the other hand, the peripheral nerves innervating the tongue showed unique structures that allowed the identification of the origin of the nerve bundles, in addition to revealing the identity of each axon within each nerve bundle. These results indicate that TLR7 may play a distinct role in the response to pathogens within the tongue, which provides a basis for further studies on the specificity of TLR7 in the peripheral nerves.

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Baccarella, A., Fontana, M., Chen, E. and Kim, C. (2013). Toll-Like Receptor 7 Mediates Early Innate Immune Responses to Malaria. Infection and Immunity, 81(12), pp.4431-4442.

Barajon, I., Serrao, G., Arnaboldi, F., Opizzi, E., Ripamonti, G., Balsari, A. and Rumio, C. (2009). Toll-like Receptors 3, 4, and 7 Are Expressed in the Enteric Nervous System and Dorsal Root Ganglia. Journal of Histochemistry & Cytochemistry, 57(11), pp.1013-1023.

Basbaum, A., Bautista, D., Scherrer, G. and Julius, D. (2009). Cellular and Molecular Mechanisms of Pain. Cell, 139(2), pp.267-284.

Bautista, D., Jordt, S., Nikai, T., Tsuruda, P., Read, A., Poblete, J., Yamoah, E., Basbaum, A. and Julius, D. (2006). TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents. Cell, 124(6), pp.1269-1282.

Bennet, D., Michael, G., Ramachandran, N., Munson, J., Averill, S., Yan, Q., McMahon, S. and Priestley, J. (1998). A Distinct Subgroup pf Small DRG Cells Express GDNF Receptor Components and GDNF Is Protective for These Neurons after Nerve Injury. The journal of Neuroscience, 18(8), pp.3059-3072.

Binch, A., Cole, A., Breakwell, L., Michael, A., Chiverton, N., Creemers, L., Cross, A. and Le Maitre, C. (2015). Nerves are more abundant than blood vessels in the degenerate human intervertebral disc. Arthritis Research & Therapy, 17(1).

Bsibsi, M., Ravid, R., Gveric, D. and van Noort, J. (2002). Broad Expression of Toll-Like Receptors in the Human Central Nervous System. Journal of Neuropathology & Experimental Neurology, 61(11), pp.1013-1021.

Cameron, J., Alexopoulou, L., Sloane, J., DiBernardo, A., Ma, Y., Kosaras, B., Flavell, R., Strittmatter, S., Volpe, J., Sidman, R. and Vartanian, T. (2007). Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in Mammals. Journal of Neuroscience, 27(47), pp.13033-13041.

Carrión, D., Korkmaz, Y., Cho, B., Kopp, M., Bloch, W., Addicks, K. and Niedermeier, W. (2015). Loss of Aβ-nerve endings associated with the Merkel cell-neurite complex in the lesional oral mucosa epithelium of lichen planus and hyperkeratosis. International Journal of Oral Science, 8(1), pp.32-38.

Dong, X., Han, S., Zylka, M., Simon, M. and Anderson, D. (2001). A Diverse Family of GPCRs Expressed in Specific Subsets of Nociceptive Sensory Neurons. Cell, 106(5), pp.619-632.

Du, X., Poltorak, A., Wei, Y. and Beutler, B. (2000). Three novel mammalian toll-like receptors: gene structure, expression, and evolution. European Cytokine Network, 11(3), pp.362-71.

Fitzgerald, M. and Law, M. (1958). The peripheral connexions between the lingual and hypoglossal nerves. Journal of Anatomy, 92(2), pp.178-188.

Funk, E., Kottilil, S., Gilliam, B. and Talwani, R. (2014). Tickling the TLR7 to cure viral hepatitis. Journal of Translational Medicine, 12(1), p.129.

Griffin, J. and Thompson, W. (2008). Biology and pathology of nonmyelinating Schwann cells. Glia, 56(14), pp.1518-1531.

Gritzmann, N. and Fruhwald, F. (1988). Sonographic anatomy of tongue and floor of the mouth. Dysphagia, 2(4), pp.196-202.

Hashimoto, C., Hudson, K. and Anderson, K. (1988). The Toll gene of drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell, 52(2), pp.269-279.

Heasman, P. and Beynon, A. (1986). Quantitative Diameter Analysis of Lingual Nerve Axons in Man. Journal of Dental Research, 65(7), pp.1016-1019.

Helley, M., Abate, W., Jackson, S., Bennett, J. and Thompson, S. (2015). The expression of Toll-like receptor 4, 7 and co-receptors in neurochemical sub-populations of rat trigeminal ganglion sensory neurons. Neuroscience, 310, pp.686-698.

Hellstrand, E. (1981). Contraction times of the cat's tongue muscles measured by light reflection. Innervation of individual tongue muscles. Acta Physiologica Scandinavica, 111(4), pp.417-423.

Imai, Y., Kuba, K., Neely, G., Yaghubian-Malhami, R., Perkmann, T., van Loo, G., Ermolaeva, M., Veldhuizen, R., Leung, Y., Wang, H., Liu, H., Sun, Y., Pasparakis, M., Kopf, M., Mech, C., Bavari, S., Peiris, J., Slutsky, A., Akira, S., Hultqvist, M., Holmdahl, R., Nicholls, J., Jiang, C., Binder, C. and Penninger, J. (2008). Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury. Cell, 133(2), pp.235-249.

Iwasaki, A. and Medzhitov, R. (2004). Toll-like receptor control of the adaptive immune responses. Nature Immunology, 5(10), pp.987-995.

Iwasaki, A. and Medzhitov, R. (2010). Regulation of Adaptive Immunity by the Innate Immune System. Science, 327(5963), pp.291-295.

Kapuscinski, J. (1995). DAPI: a DNA-Specific Fluorescent Probe. Biotechnic & Histochemistry, 70(5), pp.220-233.

Kobayashi, K., Fukuoka, T., Obata, K., Yamanaka, H., Dai, Y., Tokunaga, A. and Noguchi, K. (2005). Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with aδ/c-fibres and colocalization with trk receptors. The Journal of Comparative Neurology, 493(4), pp.596-606.

Kumar, H., Kawai, T. and Akira, S. (2009). Pathogen recognition in the innate immune response. Biochemical Journal, 420(1), pp.1-16.

Lafon, M., Megret, F., Lafage, M. and Prehaud, C. (2006). The Innate Immune Facet of Brain: Human Neurons Express TLR-3 and Sense Viral dsRNA. Journal of Molecular Neuroscience, 29(3), pp.185-194.

Lawn, A. (1966). The localization, in the nucleus ambiguus of the rabbit, of the cells of origin of motor nerve fibres in the glossopharyngeal nerve and various branches of the vagus nerve by means of retrograde degeneration. The Journal of Comparative Neurology, 127(2), pp.293-305.

Liu, T., Xu, Z., Park, C., Berta, T. and Ji, R. (2010). Toll-like receptor 7 mediates pruritus. Nature Neuroscience, 13(12), pp.1460-1462.

McClung, J. and Goldberg, S. (2000). Functional anatomy of the hypoglossal innervated muscles of the rat tongue: A model for elongation and protrusion of the mammalian tongue. The Anatomical Record, 260(4), pp.378-386.

McGilvray, I., Feld, J., Chen, L., Pattullo, V., Guindi, M., Fischer, S., Borozan, I., Xie, G., Selzner, N., Heathcote, E. and Siminovitch, K. (2012). Hepatic Cell–Type Specific Gene Expression Better Predicts HCV Treatment Outcome Than IL28B Genotype. Gastroenterology, 142(5), pp.1122-1131.e1.

Midwood, K., Sacre, S., Piccinini, A., Inglis, J., Trebaul, A., Chan, E., Drexler, S., Sofat, N., Kashiwagi, M., Orend, G., Brennan, F. and Foxwell, B. (2009). Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature Medicine, 15(7), pp.774-780.

Mishra, B., Mishra, P. and Teale, J. (2006). Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis. Journal of Neuroimmunology, 181(1-2), pp.46-56.

Molliver, D., Wright, D., Leitner, M., Parsadanian, A., Doster, K., Wen, D., Yan, Q. and Snider, W. (1997). IB4-Binding DRG Neurons Switch from NGF to GDNF Dependence in Early Postnatal Life. Neuron, 19(4), pp.849-861.

Mu, L. and Sanders, I. (1999). Neuromuscular organization of the canine tongue. The Anatomical Record, 256(4), pp.412-424.

Mu, L. and Sanders, I. (2010). Human tongue neuroanatomy: Nerve supply and motor endplates. Clinical Anatomy, 23(7), pp.777-791.

Olausson, H., Cole, J., Rylander, K., McGlone, F., Lamarre, Y., Wallin, B., Krämer, H., Wessberg, J., Elam, M., Bushnell, M. and Vallbo, Å. (2007). Functional role of unmyelinated tactile afferents in human hairy skin: sympathetic response and perceptual localization. Experimental Brain Research, 184(1), pp.135-140.

Pakdel, F., Pouralibaba, F., Pakdel, S., Khiyavi, R., Falsafi, P., Eslami, H., Fakhrzadeh, V. and Kahnamouii, S. (2015). Expression of Toll-like receptors in squamous cell carcinoma of the tongue. Scholars Research Library, 7(2), pp.20-24.

Pannese, E., Ledda, M., Cherkas, P., Huang, T. and Hanani, M. (2003). Satellite cell reactions to axon injury of sensory ganglion neurons: Increase in number of gap junctions and formation of bridges connecting previously separate perineuronal sheaths. Anatomy and Embryology, 206(5), pp.337-347.

Park, C., Xu, Z., Berta, T., Han, Q., Chen, G., Liu, X. and Ji, R. (2014). Extracellular MicroRNAs Activate Nociceptor Neurons to Elicit Pain via TLR7 and TRPA1. Neuron, 82(1), pp.47-54.

Patapoutian, A., Tate, S. and Woolf, C. (2009). Transient receptor potential channels: targeting pain at the source. Nature Reviews Drug Discovery, 8(1), pp.55-68.

Qi, J., Buzas, K., Fan, H., Cohen, J., Wang, K., Mont, E., Klinman, D., Oppenheim, J. and Howard, O. (2011). Painful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons. The Journal of Immunology, 186(11), pp.6417-6426.

Roach, J., Glusman, G., Rowen, L., Kaur, A., Purcell, M., Smith, K., Hood, L. and Aderem, A. (2005). The evolution of vertebrate Toll-like receptors. Proceedings of the National Academy of Sciences, 102(27), pp.9577-9582.

Saigusa, H., Tanuma, K., Yamashita, K., Saigusa, M. and Niimi, S. (2006). Nerve fiber analysis for the lingual nerve of the human adult subjects. Surgical and Radiologic Anatomy, 28(1), pp.59-65.

Schmelz, M., Schmidt, R., Ringkamp, M., Forster, C., Handwerker, H. and Torebjork, H. (1996). Limitation of sensitization to injured parts of receptive fields in human skin C-nociceptors. Experimental Brain Research, 109(1).

Story, G., Peier, A., Reeve, A., Eid, S., Mosbacher, J., Hricik, T., Earley, T., Hergarden, A., Andersson, D., Hwang, S., McIntyre, P., Jegla, T., Bevan, S. and Patapoutian, A. (2003). ANKTM1, a TRP-like Channel Expressed in Nociceptive Neurons, Is Activated by Cold Temperatures. Cell, 112(6), pp.819-829.

Stucky, C. and Lewin, G. (1999). Isolectin B(4)-positive and -negative nociceptors are functionally distinct. Journal of Neuroscience, 19(15), pp.6497-505.

Stutley, J., Cooke, J. and Parsons, C. (1989). Normal CT anatomy of the tongue, floor of mouth and oropharynx. Clinical Radiology, 40(3), pp.248-253.

Sugerman, P., Savage, N. and Young, W. (2000). Mucocele of the anterior lingual salivary glands (glands of Blandin and Nuhn): Report of 5 cases. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 90(4), pp.478-482.

Takeda, K., Kaisho, T. and Akira, S. (2003). TOLL-LIKE RECEPTORS. Annual Review of Immunology, 21(1), pp.335-376.

Takeuchi, O. and Akira, S. (2010). Pattern Recognition Receptors and Inflammation. Cell, 140(6), pp.805-820.

Trojanowski, J., Walkenstein, N. and Lee, V. (1986). Expression of Neurofilament Subunits in Neurons of the Central and Peripheral Nervous System: An Immunohistochemical Study with Monoclonal Antibodies. The journal of Neuroscience, 6(3), pp.650-660.

Trudler, D., Farfara, D. and Frenkel, D. (2010). Toll-Like Receptors Expression and Signaling in Glia Cells in Neuro-Amyloidogenic Diseases: Towards Future Therapeutic Application. Mediators of Inflammation, 2010, pp.1-12.

Wadachi, R. and Hargreaves, K. (2006). Trigeminal Nociceptors Express TLR-4 and CD14: a Mechanism for Pain due to Infection. Journal of Dental Research, 85(1), pp.49-53.

Wei, Y., Hu, S., Sun, B., Zhang, Q., Qiao, G., Wang, Z., Shao, R., Huang, G. and Qi, Z. (2017). Molecular cloning and expression analysis of toll-like receptor genes (TLR7, TLR8 and TLR9) of golden pompano (Trachinotus ovatus ). Fish & Shellfish Immunology, 63, pp.270-276.

West, X., Malinin, N., Merkulova, A., Tischenko, M., Kerr, B., Borden, E., Podrez, E., Salomon, R. and Byzova, T. (2010). Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature, 467(7318), pp.972-976.

Woolf, C. and Ma, Q. (2007). Nociceptors—Noxious Stimulus Detectors. Neuron, 55(3), pp.353-364.

Yamamoto, T. (1975). Linguo-hypoglossal reflex: effects of mechanical, thermal and taste stimuli. Brain Research, 92(3), pp.499-504.

Zhao, H., Halicka, H., Traganos, F., Jorgensen, E. and Darzynkiewicz, Z. (2010). New biomarkers probing depth of cell senescence assessed by laser scanning cytometry. Cytometry Part A, 77A(11), pp.999-1007.

Zur, K., Mu, L. and Sanders, I. (2004). Distribution pattern of the human lingual nerve. Clinical Anatomy, 17(2), pp.88-92.


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