TLR Signalling: Beyond Immunity


The ability of multicellular organisms to detect and eliminate pathogens is key to their survival. Toll‐like receptors (TLRs) are one of the key components of the immune response in invertebrates and vertebrates. Although the general families of TLRs are conserved between species in the detection of microbe‐associated molecular patterns, their specific role may be altered in these distinct organisms. Beyond the vast role of TLRs in immunity, they are also involved in development, metabolic homoeostasis and pain sensation.

Key Concepts

  • The role of TLRs in facilitating the innate immune response is well established, but they are now known to be involved in development, metabolic homoeostasis and nociception.
  • TLRs are functionally conserved between species but can play different roles depending on the tissue in which they are expressed as well as the nature of the activating ligand and downstream effectors.
  • TLRs use two main adaptor proteins to facilitate their downstream signalling pathways: Myd88 dependent and TRIF.
  • The ligands recognised by TLRs can be described as microbe‐associated molecular patterns (MAMPs) and damage‐associated molecular patterns (DAMPs).
  • TLRs have been targeted for therapeutic applications, but a balance must be struck between their inhibition and activation to maintain homoeostasis.

Keywords: Toll‐like receptors; damage‐associated molecular patterns; microbe‐associated molecular pattern; Myd88

Figure 1. Schematic of TLR and PRR pathways in metazoans and plants, respectively. There are two main pathways utilised in TLR signalling for metazoans: myd88 dependent/independent. The figure depicts both pathways as well as the ligands which activate them for metazoans, while only myd88 is found in invertebrates, and plants forgo myd88 altogether. Homologous intermediates that function in these pathways are coloured similarly as well and signal through similar downstream transcription factors to bring about conserved outcomes related to immunity such as inflammation.


Alexopoulou L, Thomas V, Schnare M, et al. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1‐ and TLR2‐deficient mice. Nature Medicine 8: 878–884.

Asai T, Tena G, Plotnikova J, et al. (2002) MAP kinase signalling cascade in Arabidopsis innate immunity. Nature 415: 977–983.

Ausubel FM (2005) Are innate immune signaling pathways in plants and animals conserved? Nature Immunology 6: 973–979.

Barak B, Feldman N and Okun E (2014) Toll‐like receptors as developmental tools that regulate neurogenesis during development: an update. Frontiers in Neuroscience 8: 272.

Behera AK, Hildebrand E, Bronson RT, et al. (2006) MyD88 deficiency results in tissue‐specific changes in cytokine induction and inflammation in interleukin‐18‐independent mice infected with Borrelia burgdorferi. Infection and Immunity 74 (1): 1462–1470.

Botos I, Segal DM and Davies DR (2011) The structural biology of toll‐like receptors. Structure 19 (4): 447–459.

Caesar R, Tremaroli V, Kovatcheva‐Datchary P, et al. (2015) Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metabolism 22: 658–668.

Cho SK, Larue CT, Chevalier D, et al. (2008) Regulation of floral organ abscission in Arabidopsis thaliana. Proceedings of the National Academy of Sciences of the United States of America 105 (40): 15629–15634.

Clouse SD (2011) Brassinosteroid signal transduction: from receptor kinase activation to transcriptional networks regulating plant development. The Plant Cell 23 (4): 1219–1230.

Den Haan JMM, Lehar SM and Bevan MJ (2000) CD8+ but not CD8‐ dendritic cells cross‐prime cytotoxic T cells in vivo. Journal of Experimental Medicine 192 (12): 1685–1696.

Feinlay BB and McFadden G (2006) Anti‐immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124 (4): 767–782.

Fornsková A, Vinkler M, Pagés M, et al. (2013) Contrasted evolutionary histories of two Toll‐like receptors (Tlr4 and Tlr7) in wild rodents (MURINAE). BMC Evolutionary Biology 13: 194.

Gelman AE, Zhang J, Choi Y, et al. (2004) Toll‐like receptor ligands directly promote activated CD4+ T cell survival. The Journal of Immunology 172 (10): 6065–6073.

Gómez‐Gómez L and Boller T (2000) FLS2: an LRR receptor‐like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Molecular Cell 5: 1003–1011.

Gómez‐Gómez L and Boller T (2002) Flagellin perception: a paradigm for innate immunity. Trends in Plant Science 7: 251–256.

Greenberg S and Grinstein S (2002) Phagocytosis and innate immunity. Current Opinion in Immunology 14 (1): 136–145.

Gubert CM and Liljegren SJ (2014) HAESA and HAESA‐LIKE2 activate organ abscission downstream of NEVERSHED and EVERSHED in Arabidopsis flowers. Plant Signaling & Behavior 9 (7): e29115.

Hanson GK and Edfelt K (2005) Toll to be paid at the gateway to the vessel wall. Arteriosclerosis, Thrombosis, and Vascular Biology 25 (6): 1085–1087.

Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444: 860–867.

Ji Y, Sun S, Goodrich JK, et al. (2014) Diet‐induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4‐deficient mice. Cell Reports 8 (1): 137–149.

Jinn TL, Stone JM and Walker JC (2000) HAESA, an Arabidopsis leucine‐rich repeat receptor kinase, controls floral organ abscission. Genes & Development 14: 108–117.

Kambris Z, Hoffmann JA, Imler J‐L, et al. (2002) Tissue and stage‐specific expression of the Tolls in Drosophila embryos. Gene Expression Patterns 2 (3–4): 311–317.

Kim D, Kim A, Cho IH, et al. (2007) A critical role of toll‐like receptor 2 in nerve injury‐induced spinal cord glial cell activation and pain hypersensitivity. Journal of Biological Chemistry 282 (20): 14975–14983.

Konner AC and Bruning JC (2011) Toll‐like receptors: linking inflammation to metabolism. Trends in Endocrinology and Metabolism 22 (1): 16–23.

Kubinak JL and Round JL (2012) Toll‐like receptors promote mutually beneficial commensal–host interactions. PLoS Pathogens 8 (7): 242–252.

Lahiri A, Das P and Chakravortty D (2008) Engagement of TLR signaling as adjuvant: towards smarter vaccine and beyond. Vaccine 26 (52): 6777–6783.

Lam E, Kato N and Lawton M (2001) Programmed cell death, mitochondria and the plant hypersensitive response. Nature 411: 848–853.

Lathia JD, Okun E, Tang SC, et al. (2008) Toll‐like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. Journal of Neuroscience 28 (51): 13978–13984.

Lozano‐Durán R and Zipfel C (2015) Trade‐off between growth and immunity: role of brassinosteroids. Trends in Plant Science 20 (1): 12–19.

Mai CW, Kang YB and Pichika MR (2013) Should a Toll‐like receptor 4 (TLR‐4) agonist or antagonist be designed to treat cancer? TLR‐4: its expression and effects in the ten most common cancers. OncoTargets and Therapy 6: 1573–1587.

McIlroy G, Foldi I, Aurikko J, et al. (2013) Toll‐6 and Toll‐7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nature Neuroscience 16 (9): 1248–1256.

Medzhitov R (2001) Toll‐like receptors and innate immunity. Nature Reviews Immunology 1 (2): 135–145.

Meng X, Zhou J, Tang J, et al. (2016) Ligand‐induced receptor‐like kinase complex regulates floral organ abscission in Arabidopsis. Cell Reports 14: 1330–1338.

O'Neill LAJ and Bowie AG (2007) The family of five: TIR‐domain‐containing adaptors in toll‐like receptor signalling. Nature Reviews Immunology 7 (5): 353–364.

Okun E, Griffioen KJ and Mattson MP (2011) Toll‐like receptor signaling in neural plasticity and disease. Trends in Neurosciences 34 (5): 269–281.

Okun E, Barak B, Saada‐Madar R, et al. (2012) Evidence for a developmental role for TLR4 in learning and memory. PLoS ONE 7 (10): 1–8.

Osterloh JM, Yang J, Rooney TM, et al. (2012) dSarm/Sarm1 is required for activation of an injury‐induced axon death pathway. Science 337: 481–484.

Rakoff‐Nahoum S and Medzhitov R (2009) Toll‐like receptors and cancer. Nature Reviews Cancer 9 (1): 57–63.

Reyna SM, Ghosh S, Tantiwong P, et al. (2008) Elevated toll‐like receptor 4 expression and signaling in muscle from insulin‐resistant subjects. Diabetes 57: 2595–2602.

Round JL, Lee SM, Li J, et al. (2011) The Toll‐like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332: 974–977.

Scholz J and Woolf CJ (2007) The neuropathic pain triad: neurons, immune cells and glia. Nature Neuroscience 10 (11): 1361–1368.

Silverman N and Maniatis T (2001) NF‐κB signaling pathways in mammalian and insect innate immunity. Genes & Development 15 (18): 2321–2342.

Takeda K and Akira S (2004) TLR signalling pathways. International Immunology 17 (1): 1–14.

Takeda K, Kaisho T and Akira S (2003) Toll‐like receptors. Annual Review of Immunology 21: 335–376.

Takeuchi O, Sato S, Horiuchi T, et al. (2002) Cutting edge: role of Toll‐like receptor 1 in mediating immune response to microbial lipoproteins. Journal of Immunology 169: 10–14.

Thakur KK, Saini J, Mahajan K, et al. (2016) Therapeutic implications of toll‐like receptors in peripheral neuropathic pain. Pharmacological Research 115: 224–232.

Toussi DN and Massari P (2014) Immune adjuvant effect of molecularly‐defined Toll‐like receptor ligands. Vaccines 2 (2): 323–353.

Turnbaugh PJ, Ley RE, Mahowald MA, et al. (2006) An obesity‐associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027–1031.

Vijay‐Kumar M, Aitken JD, Carvalho FA, et al. (2010) Metabolic syndrome and altered gut microbiota in mice lacking Toll‐like receptor 5. Science 328: 228–231.

Vitseva OI, Tanriverdi K, Tchkonia TT, et al. (2008) Inducible toll‐like receptor and NF‐kB regulatory pathway expression in human adipose tissue. Obesity 16: 932–937.

Yu L, Wang L and Chen S (2010) Endogenous toll‐like receptor ligands and their biological significance. Journal of Cellular and Molecular Medicine 14 (11): 2592–2603.

Further Reading

Antolín‐Llovera M, Petutsching EK, Ried MK, et al. (2014) Knowing your friends and foes – plant receptor‐like kinases as initiators of symbiosis or defence. New Phytologist 204 (4): 791–802.

Haney CH, Urbach J and Ausubel FM (2014) Innate immunity in plants and animals. The Biochemist 36 (5): 40–44.

Morisato D and Anderson KV (1995) Signaling pathways that establish the dorsal–ventral pattern of the Drosophila embryo. Annual Review of Genetics 29: 371–399.

Roach J, Glusman G, Rowen L, et al. (2005) The evolution of vertebrate Toll‐like receptors. Proceedings of the National Academy of Sciences of the United States of America 102 (27): 9577–9582.

Ronald PC and Beutler B (2010) Plant and animal sensors of conserved microbial signatures. Science 330: 1061–1064.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Guessoum, Omar, Tang, Qijun, Agorsor, Israel DK, Ke, Wenfan, Li, Renyu, Danna, Cristian H, and Deppmann, Christopher D(Aug 2017) TLR Signalling: Beyond Immunity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027502]