{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:11:51Z","timestamp":1793157111913,"version":"4.5.0"},"reference-count":89,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Migraine is a complex neurological disease of unknown etiology involving both genetic and environmental factors. It has previously been reported that persistent pain may be mediated by the immune and inflammatory systems. Toll-like receptors (TLRs) play a significant role in immune and inflammatory responses and are expressed by microglia and astrocytes. One of the fundamental mechanisms of the innate immune system in coordinating inflammatory signal transduction is through TLRs, which protect the host organism by initiating inflammatory signaling cascades in response to tissue damage or stress. TLRs reside at the neuroimmune interface, and accumulating evidence has suggested that the inflammatory consequences of TLR activation on glia (mainly microglia and astrocytes), sensory neurons, and other cell types can influence nociceptive processing and lead to pain. Several studies have shown that TLRs may play a key role in neuropathic pain and migraine etiology by activating the microglia. The pathogenesis of migraine may involve a TLR-mediated crosstalk between neurons and immune cells. Innate responses in the central nervous system (CNS) occur during neuroinflammatory phenomena, including migraine. Antigens found in the environment play a crucial role in the inflammatory response, causing a broad range of diseases, including migraines. These can be recognized by several innate immune cells, including macrophages, microglia, and dendritic cells, and can be activated through TLR signaling. Given the prevalence of migraine and the insufficient efficacy and safety of current treatment options, a deeper understanding of TLRs is expected to provide novel therapies for managing chronic migraine. This review aimed to justify the view that TLRs may be involved in migraine.<\/jats:p>","DOI":"10.1186\/s13041-022-00960-5","type":"journal-article","created":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T02:03:41Z","timestamp":1660961021000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Toll-like receptors and their role in neuropathic pain and migraine"],"prefix":"10.1186","volume":"15","author":[{"given":"Xuejiao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longde","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1620-7351","authenticated-orcid":false,"given":"Zhaoming","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,8,20]]},"reference":[{"issue":"10","key":"960_CR1","doi-asserted-by":"publisher","first-page":"5087","DOI":"10.1007\/s12325-021-01781-z","volume":"38","author":"L Harris","year":"2021","unstructured":"Harris L, L\u2019Italien G, O\u2019Connell T, Hasan Z, Hutchinson S, Lucas S. A framework for estimating the eligible patient population for new migraine acute therapies in the United States. Adv Ther. 2021;38(10):5087\u201397.","journal-title":"Adv Ther"},{"issue":"6","key":"960_CR2","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41582-018-0003-1","volume":"14","author":"L Edvinsson","year":"2018","unstructured":"Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies\u2014successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338\u201350.","journal-title":"Nat Rev Neurol"},{"issue":"10100","key":"960_CR3","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1016\/S0140-6736(17)32154-2","volume":"390","author":"regional Global","year":"2017","unstructured":"Global regional. and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211\u201359.","journal-title":"Lancet"},{"issue":"2","key":"960_CR4","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s12264-012-1219-5","volume":"28","author":"T Liu","year":"2012","unstructured":"Liu T, Gao YJ, Ji RR. Emerging role of toll-like receptors in the control of pain and itch. Neurosci Bull. 2012;28(2):131\u201344.","journal-title":"Neurosci Bull"},{"issue":"3","key":"960_CR5","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1007\/s13311-014-0278-x","volume":"11","author":"EA Pereira","year":"2014","unstructured":"Pereira EA, Aziz TZ. Neuropathic pain and deep brain stimulation. Neurotherapeutics. 2014;11(3):496\u2013507.","journal-title":"Neurotherapeutics"},{"issue":"10","key":"960_CR6","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1016\/j.pain.2011.06.017","volume":"152","author":"TS Jensen","year":"2011","unstructured":"Jensen TS, Baron R, Haanp\u00e4\u00e4 M, Kalso E, Loeser JD, Rice ASC, et al. A new definition of neuropathic pain. Pain. 2011;152(10):2204\u20135.","journal-title":"Pain"},{"issue":"4","key":"960_CR7","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.jpain.2005.11.008","volume":"7","author":"N Torrance","year":"2006","unstructured":"Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7(4):281\u20139.","journal-title":"J Pain"},{"issue":"3","key":"960_CR8","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.pain.2007.08.013","volume":"136","author":"D Bouhassira","year":"2008","unstructured":"Bouhassira D, Lant\u00e9ri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380\u20137.","journal-title":"Pain"},{"issue":"1","key":"960_CR9","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s12974-020-1731-x","volume":"17","author":"H Yang","year":"2020","unstructured":"Yang H, Wu L, Deng H, Chen Y, Zhou H, Liu M, et al. Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2\/MyD88\/NF-\u03baB signaling pathway in spinal microglia. J Neuroinflamm. 2020;17(1):154.","journal-title":"J Neuroinflamm"},{"issue":"6","key":"960_CR10","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1172\/JCI45414","volume":"122","author":"T Liu","year":"2012","unstructured":"Liu T, Berta T, Xu ZZ, Park CK, Zhang L, L\u00fc N, et al. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest. 2012;122(6):2195\u2013207.","journal-title":"J Clin Invest"},{"issue":"2","key":"960_CR11","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1007\/s11064-016-2119-2","volume":"42","author":"W Chen","year":"2017","unstructured":"Chen W, Lu Z. Upregulated TLR3 promotes neuropathic pain by regulating autophagy in rat with L5 spinal nerve ligation model. Neurochem Res. 2017;42(2):634\u201343.","journal-title":"Neurochem Res"},{"key":"960_CR12","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/1742-2094-10-148","volume":"10","author":"JA Stokes","year":"2013","unstructured":"Stokes JA, Cheung J, Eddinger K, Corr M, Yaksh TL. Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice. J Neuroinflamm. 2013;10:148.","journal-title":"J Neuroinflamm"},{"issue":"23","key":"960_CR13","doi-asserted-by":"publisher","first-page":"5917","DOI":"10.3390\/ijms20235917","volume":"20","author":"Y Li","year":"2019","unstructured":"Li Y, Yin C, Li X, Liu B, Wang J, Zheng X, et al. Electroacupuncture alleviates paclitaxel-induced peripheral neuropathic pain in rats via suppressing TLR4 signaling and TRPV1 upregulation in sensory neurons. Int J Mol Sci. 2019;20(23):5917.","journal-title":"Int J Mol Sci."},{"issue":"11","key":"960_CR14","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1038\/nm.3978","volume":"21","author":"ZZ Xu","year":"2015","unstructured":"Xu ZZ, Kim YH, Bang S, Zhang Y, Berta T, Wang F, et al. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015;21(11):1326\u201331.","journal-title":"Nat Med"},{"key":"960_CR15","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.bbi.2020.03.019","volume":"87","author":"L He","year":"2020","unstructured":"He L, Han G, Wu S, Du S, Zhang Y, Liu W, et al. Toll-like receptor 7 contributes to neuropathic pain by activating NF-\u03baB in primary sensory neurons. Brain Behav Immun. 2020;87:840\u201351.","journal-title":"Brain Behav Immun"},{"issue":"12","key":"960_CR16","doi-asserted-by":"publisher","first-page":"3019","DOI":"10.1084\/jem.20180800","volume":"215","author":"ZJ Zhang","year":"2018","unstructured":"Zhang ZJ, Guo JS, Li SS, Wu XB, Cao DL, Jiang BC, et al. TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J Exp Med. 2018;215(12):3019\u201337.","journal-title":"J Exp Med"},{"issue":"35","key":"960_CR17","doi-asserted-by":"publisher","first-page":"6848","DOI":"10.1523\/JNEUROSCI.3257-18.2019","volume":"39","author":"X Luo","year":"2019","unstructured":"Luo X, Huh Y, Bang S, He Q, Zhang L, Matsuda M, et al. Macrophage toll-like receptor 9 contributes to chemotherapy-induced neuropathic pain in male mice. J Neurosci. 2019;39(35):6848\u201364.","journal-title":"J Neurosci"},{"key":"960_CR18","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.pharmthera.2017.10.006","volume":"184","author":"MJ Lacagnina","year":"2018","unstructured":"Lacagnina MJ, Watkins LR, Grace PM. Toll-like receptors and their role in persistent pain. Pharmacol Ther. 2018;184:145\u201358.","journal-title":"Pharmacol Ther"},{"issue":"5","key":"960_CR19","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.immuni.2011.05.006","volume":"34","author":"T Kawai","year":"2011","unstructured":"Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637\u201350.","journal-title":"Immunity"},{"issue":"3","key":"960_CR20","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/0092-8674(85)90275-2","volume":"42","author":"KV Anderson","year":"1985","unstructured":"Anderson KV, Bokla L, N\u00fcsslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell. 1985;42(3):791\u20138.","journal-title":"Cell"},{"issue":"6325","key":"960_CR21","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/351355b0","volume":"351","author":"NJ Gay","year":"1991","unstructured":"Gay NJ, Keith FJ. Drosophila Toll and IL-1 receptor. Nature. 1991;351(6325):355\u20136.","journal-title":"Nature"},{"issue":"1","key":"960_CR22","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1006\/bbrc.1995.1477","volume":"209","author":"M Rosetto","year":"1995","unstructured":"Rosetto M, Engstr\u00f6m Y, Baldari CT, Telford JL, Hultmark D. Signals from the IL-1 receptor homolog, Toll, can activate an immune response in a Drosophila hemocyte cell line. Biochem Biophys Res Commun. 1995;209(1):111\u20136.","journal-title":"Biochem Biophys Res Commun"},{"issue":"6640","key":"960_CR23","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/41131","volume":"388","author":"R Medzhitov","year":"1997","unstructured":"Medzhitov R, Preston-Hurlburt P, Janeway CA.Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394\u20137.","journal-title":"Nature"},{"issue":"6","key":"960_CR24","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nri3446","volume":"13","author":"LA O\u2019Neill","year":"2013","unstructured":"O\u2019Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors\u2014redefining innate immunity. Nat Rev Immunol. 2013;13(6):453\u201360.","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"960_CR25","doi-asserted-by":"publisher","first-page":"e21","DOI":"10.4110\/in.2020.20.e21","volume":"20","author":"F Fore","year":"2020","unstructured":"Fore F, Indriputri C, Mamutse J, Nugraha J. TLR10 and its unique anti-inflammatory properties and potential use as a target in therapeutics. Immune Netw. 2020;20(3):e21.","journal-title":"Immune Netw"},{"issue":"1","key":"960_CR26","doi-asserted-by":"publisher","first-page":"a011247","DOI":"10.1101\/cshperspect.a011247","volume":"5","author":"KH Lim","year":"2013","unstructured":"Lim KH, Staudt LM. Toll-like receptor signaling. Cold Spring Harb Perspect Biol. 2013;5(1):a011247.","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"3","key":"960_CR27","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.immuni.2010.03.012","volume":"32","author":"AL Blasius","year":"2010","unstructured":"Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32(3):305\u201315.","journal-title":"Immunity"},{"issue":"1","key":"960_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.coi.2009.12.002","volume":"22","author":"AF McGettrick","year":"2010","unstructured":"McGettrick AF, O\u2019Neill LA. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol. 2010;22(1):20\u20137.","journal-title":"Curr Opin Immunol"},{"issue":"2","key":"960_CR29","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1111\/j.1471-4159.2010.06778.x","volume":"114","author":"E Okun","year":"2010","unstructured":"Okun E, Griffioen KJ, Son TG, Lee JH, Roberts NJ, Mughal MR, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation. J Neurochem. 2010;114(2):462\u201374.","journal-title":"J Neurochem"},{"issue":"51","key":"960_CR30","doi-asserted-by":"publisher","first-page":"13978","DOI":"10.1523\/JNEUROSCI.2140-08.2008","volume":"28","author":"JD Lathia","year":"2008","unstructured":"Lathia JD, Okun E, Tang SC, Griffioen K, Cheng A, Mughal MR, et al. Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci. 2008;28(51):13978\u201384.","journal-title":"J Neurosci"},{"issue":"9","key":"960_CR31","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1038\/ncb1629","volume":"9","author":"A Rolls","year":"2007","unstructured":"Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol. 2007;9(9):1081\u20138.","journal-title":"Nat Cell Biol"},{"issue":"25","key":"960_CR32","doi-asserted-by":"publisher","first-page":"11555","DOI":"10.1073\/pnas.1006496107","volume":"107","author":"JA Sloane","year":"2010","unstructured":"Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A. 2010;107(25):11555\u201360.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"960_CR33","first-page":"33","volume":"10","author":"JW Zhu","year":"2016","unstructured":"Zhu JW, Li YF, Wang ZT, Jia WQ, Xu RX. Toll-like receptor 4 deficiency impairs motor coordination. Front Neurosci. 2016;10:33.","journal-title":"Front Neurosci"},{"issue":"9","key":"960_CR34","doi-asserted-by":"publisher","first-page":"dev156018","DOI":"10.1242\/dev.156018","volume":"145","author":"N Anthoney","year":"2018","unstructured":"Anthoney N, Foldi I, Hidalgo A. Toll and Toll-like receptor signalling in development. Development. 2018;145(9):dev156018.","journal-title":"Development"},{"issue":"1","key":"960_CR35","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.smim.2003.10.003","volume":"16","author":"K Takeda","year":"2004","unstructured":"Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16(1):3\u20139.","journal-title":"Semin Immunol"},{"issue":"5","key":"960_CR36","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/ni.1863","volume":"11","author":"T Kawai","year":"2010","unstructured":"Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373\u201384.","journal-title":"Nat Immunol"},{"issue":"11","key":"960_CR37","doi-asserted-by":"publisher","first-page":"a011254","DOI":"10.1101\/cshperspect.a011254","volume":"4","author":"DK Morrison","year":"2012","unstructured":"Morrison DK. MAP kinase pathways. Cold Spring Harb Perspect Biol. 2012;4(11):a011254.","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"9","key":"960_CR38","doi-asserted-by":"publisher","first-page":"3834","DOI":"10.4049\/jimmunol.1502599","volume":"196","author":"S Jiang","year":"2016","unstructured":"Jiang S, Li X, Hess NJ, Guan Y, Tapping RI. TLR10 is a negative regulator of both MyD88-dependent and -independent TLR signaling. J Immunol. 2016;196(9):3834\u201341.","journal-title":"J Immunol"},{"issue":"6832","key":"960_CR39","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/35074106","volume":"410","author":"F Hayashi","year":"2001","unstructured":"Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410(6832):1099\u2013103.","journal-title":"Nature"},{"issue":"1","key":"960_CR40","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s10194-021-01254-2","volume":"22","author":"WJ Chen","year":"2021","unstructured":"Chen WJ, Niu JQ, Chen YT, Deng WJ, Xu YY, Liu J, et al. Unilateral facial injection of Botulinum neurotoxin A attenuates bilateral trigeminal neuropathic pain and anxiety-like behaviors through inhibition of TLR2-mediated neuroinflammation in mice. J Headache Pain. 2021;22(1):38.","journal-title":"J Headache Pain"},{"issue":"1","key":"960_CR41","doi-asserted-by":"publisher","first-page":"115","DOI":"10.4049\/jimmunol.2100115","volume":"207","author":"P Samir","year":"2021","unstructured":"Samir P, Place DE, Malireddi RKS, Kanneganti TD. TLR and IKK complex-mediated innate immune signaling inhibits stress granule assembly. J Immunol. 2021;207(1):115\u201324.","journal-title":"J Immunol"},{"issue":"7147","key":"960_CR42","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1038\/nature05836","volume":"447","author":"SL Foster","year":"2007","unstructured":"Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447(7147):972\u20138.","journal-title":"Nature"},{"issue":"3","key":"960_CR43","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.jhep.2013.03.033","volume":"59","author":"C Brenner","year":"2013","unstructured":"Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583\u201394.","journal-title":"J Hepatol"},{"issue":"6","key":"960_CR44","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1002\/ana.24665","volume":"79","author":"CJ Perry","year":"2016","unstructured":"Perry CJ, Blake P, Buettner C, Papavassiliou E, Schain AJ, Bhasin MK, et al. Upregulation of inflammatory gene transcripts in periosteum of chronic migraineurs: implications for extracranial origin of headache. Ann Neurol. 2016;79(6):1000\u201313.","journal-title":"Ann Neurol"},{"issue":"3","key":"960_CR45","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1177\/0271678X16647398","volume":"37","author":"T Takizawa","year":"2017","unstructured":"Takizawa T, Shibata M, Kayama Y, Shimizu T, Toriumi H, Ebine T, et al. High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression. J Cereb Blood Flow Metab. 2017;37(3):890\u2013901.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"960_CR46","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s12035-014-8995-z","volume":"53","author":"A Ghaemi","year":"2016","unstructured":"Ghaemi A, Sajadian A, Khodaie B, Lotfinia AA, Lotfinia M, Aghabarari A, et al. Immunomodulatory effect of toll-like receptor-3 ligand poly I:C on cortical spreading depression. Mol Neurobiol. 2016;53(1):143\u201354.","journal-title":"Mol Neurobiol"},{"issue":"18","key":"960_CR47","doi-asserted-by":"publisher","first-page":"10134","DOI":"10.3390\/ijms221810134","volume":"22","author":"M Fila","year":"2021","unstructured":"Fila M, Chojnacki J, Pawlowska E, Szczepanska J, Chojnacki C, Blasiak J. Kynurenine pathway of tryptophan metabolism in migraine and functional gastrointestinal disorders. Int J Mol Sci. 2021;22(18):10134.","journal-title":"Int J Mol Sci."},{"key":"960_CR48","doi-asserted-by":"publisher","first-page":"174480691986784","DOI":"10.1177\/1744806919867842","volume":"15","author":"R Ramachandran","year":"2019","unstructured":"Ramachandran R, Wang Z, Saavedra C, DiNardo A, Corr M, Powell SB, et al. Role of Toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway. Mol Pain. 2019;15:1744806919867842.","journal-title":"Mol Pain"},{"issue":"1","key":"960_CR49","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s10194-021-01271-1","volume":"22","author":"O Kursun","year":"2021","unstructured":"Kursun O, Yemisci M, van den Maagdenberg A, Karatas H. Migraine and neuroinflammation: the inflammasome perspective. J Headache Pain. 2021;22(1):55.","journal-title":"J Headache Pain"},{"issue":"6123","key":"960_CR50","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1126\/science.1231897","volume":"339","author":"H Karatas","year":"2013","unstructured":"Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Ko\u00e7ak E, Sen ZD, et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013;339(6123):1092\u20135.","journal-title":"Science"},{"key":"960_CR51","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ejphar.2018.12.004","volume":"844","author":"P Conti","year":"2019","unstructured":"Conti P, D\u2019Ovidio C, Conti C, Gallenga CE, Lauritano D, Caraffa A, et al. Progression in migraine: role of mast cells and pro-inflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87\u201394.","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"960_CR52","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.4049\/jimmunol.167.4.2250","volume":"167","author":"V Supajatura","year":"2001","unstructured":"Supajatura V, Ushio H, Nakao A, Okumura K, Ra C, Ogawa H. Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. J Immunol. 2001;167(4):2250\u20136.","journal-title":"J Immunol"},{"issue":"7","key":"960_CR53","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1007\/s10072-012-1218-3","volume":"34","author":"A Cseh","year":"2013","unstructured":"Cseh A, Farkas KM, Derzbach L, Muller K, Vasarhelyi B, Szalay B, et al. Lymphocyte subsets in pediatric migraine. Neurol Sci. 2013;34(7):1151\u20135.","journal-title":"Neurol Sci"},{"issue":"5428","key":"960_CR54","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1126\/science.285.5428.736","volume":"285","author":"AO Aliprantis","year":"1999","unstructured":"Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science. 1999;285(5428):736\u20139.","journal-title":"Science"},{"issue":"6","key":"960_CR55","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1016\/j.cell.2007.09.008","volume":"130","author":"MS Jin","year":"2007","unstructured":"Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130(6):1071\u201382.","journal-title":"Cell"},{"issue":"6","key":"960_CR56","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.immuni.2009.09.018","volume":"31","author":"JY Kang","year":"2009","unstructured":"Kang JY, Nan X, Jin MS, Youn SJ, Ryu YH, Mah S, et al. Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity. 2009;31(6):873\u201384.","journal-title":"Immunity"},{"issue":"3","key":"960_CR57","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nri3151","volume":"12","author":"CC Lee","year":"2012","unstructured":"Lee CC, Avalos AM, Ploegh HL. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol. 2012;12(3):168\u201379.","journal-title":"Nat Rev Immunol"},{"issue":"11","key":"960_CR58","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/nm1315","volume":"11","author":"D Jiang","year":"2005","unstructured":"Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173\u20139.","journal-title":"Nat Med"},{"issue":"6","key":"960_CR59","doi-asserted-by":"publisher","first-page":"e102214","DOI":"10.15252\/embj.2019102214","volume":"39","author":"H Lim","year":"2020","unstructured":"Lim H, Lee J, You B, Oh JH, Mok HJ, Kim YS, et al. GT1b functions as a novel endogenous agonist of toll-like receptor 2 inducing neuropathic pain. EMBO J. 2020;39(6):e102214.","journal-title":"EMBO J"},{"issue":"9","key":"960_CR60","doi-asserted-by":"publisher","first-page":"7370","DOI":"10.1074\/jbc.M306793200","volume":"279","author":"JS Park","year":"2004","unstructured":"Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004;279(9):7370\u20137.","journal-title":"J Biol Chem"},{"issue":"8","key":"960_CR61","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1172\/JCI23755","volume":"115","author":"L Schaefer","year":"2005","unstructured":"Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest. 2005;115(8):2223\u201333.","journal-title":"J Clin Invest"},{"issue":"33","key":"960_CR62","doi-asserted-by":"publisher","first-page":"31332","DOI":"10.1074\/jbc.M103217200","volume":"276","author":"RM Vabulas","year":"2001","unstructured":"Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, H\u00e4cker H, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll\/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001;276(33):31332\u20139.","journal-title":"J Biol Chem"},{"key":"960_CR63","doi-asserted-by":"publisher","first-page":"572","DOI":"10.3389\/fimmu.2015.00572","volume":"6","author":"RS Barua","year":"2015","unstructured":"Barua RS, Sharma M, Dileepan KN. Cigarette smoke amplifies inflammatory response and atherosclerosis progression through activation of the H1R-TLR2\/4-COX2 axis. Front Immunol. 2015;6:572.","journal-title":"Front Immunol"},{"issue":"11","key":"960_CR64","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1093\/jnen\/61.11.1013","volume":"61","author":"M Bsibsi","year":"2002","unstructured":"Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61(11):1013\u201321.","journal-title":"J Neuropathol Exp Neurol"},{"issue":"8","key":"960_CR65","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1172\/JCI18696","volume":"112","author":"J Fan","year":"2003","unstructured":"Fan J, Frey RS, Malik AB. TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase. J Clin Invest. 2003;112(8):1234\u201343.","journal-title":"J Clin Invest"},{"issue":"6","key":"960_CR66","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","volume":"173","author":"JK Olson","year":"2004","unstructured":"Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173(6):3916\u201324.","journal-title":"J Immunol"},{"issue":"2","key":"960_CR67","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1002\/glia.21093","volume":"59","author":"XQ Shi","year":"2011","unstructured":"Shi XQ, Zekki H, Zhang J. The role of TLR2 in nerve injury-induced neuropathic pain is essentially mediated through macrophages in peripheral inflammatory response. Glia. 2011;59(2):231\u201341.","journal-title":"Glia"},{"issue":"36","key":"960_CR68","doi-asserted-by":"publisher","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","volume":"34","author":"Y Zhang","year":"2014","unstructured":"Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O\u2019Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929\u201347.","journal-title":"J Neurosci"},{"issue":"5","key":"960_CR69","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1159\/000225990","volume":"1","author":"G Naert","year":"2009","unstructured":"Naert G, Laflamme N, Rivest S. Toll-like receptor 2-independent and MyD88-dependent gene expression in the mouse brain. J Innate Immun. 2009;1(5):480\u201393.","journal-title":"J Innate Immun"},{"issue":"2","key":"960_CR70","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1159\/000073709","volume":"132","author":"JS Marshall","year":"2003","unstructured":"Marshall JS, McCurdy JD, Olynych T. Toll-like receptor-mediated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol. 2003;132(2):87\u201397.","journal-title":"Int Arch Allergy Immunol"},{"issue":"1","key":"960_CR71","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1556\/2060.104.2017.1.8","volume":"104","author":"E Kilinc","year":"2017","unstructured":"Kilinc E, Dagistan Y, Kotan B, Cetinkaya A. Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats. Physiol Int. 2017;104(1):15\u201324.","journal-title":"Physiol Int"},{"issue":"6857","key":"960_CR72","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/35099560","volume":"413","author":"L Alexopoulou","year":"2001","unstructured":"Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413(6857):732\u20138.","journal-title":"Nature"},{"issue":"11","key":"960_CR73","doi-asserted-by":"publisher","first-page":"6417","DOI":"10.4049\/jimmunol.1001241","volume":"186","author":"J Qi","year":"2011","unstructured":"Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011;186(11):6417\u201326.","journal-title":"J Immunol"},{"issue":"1","key":"960_CR74","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1159\/000324293","volume":"19","author":"XP Mei","year":"2011","unstructured":"Mei XP, Zhou Y, Wang W, Tang J, Wang W, Zhang H, et al. Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals. 2011;19(1):44\u201353.","journal-title":"Neurosignals"},{"issue":"9","key":"960_CR75","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nri3495","volume":"13","author":"JS Arthur","year":"2013","unstructured":"Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13(9):679\u201392.","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"960_CR76","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/S1097-2765(00)80136-7","volume":"2","author":"R Medzhitov","year":"1998","unstructured":"Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll\/IL-1 receptor family signaling pathways. Mol Cell. 1998;2(2):253\u20138.","journal-title":"Mol Cell"},{"issue":"7030","key":"960_CR77","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nature03308","volume":"434","author":"A Takaoka","year":"2005","unstructured":"Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434(7030):243\u20139.","journal-title":"Nature"},{"issue":"5","key":"960_CR78","doi-asserted-by":"publisher","first-page":"2906","DOI":"10.1016\/S0021-9258(18)32804-7","volume":"258","author":"SM Strain","year":"1983","unstructured":"Strain SM, Fesik SW, Armitage IM. Characterization of lipopolysaccharide from a heptoseless mutant of Escherichia coli by carbon 13 nuclear magnetic resonance. J Biol Chem. 1983;258(5):2906\u201310.","journal-title":"J Biol Chem"},{"issue":"1","key":"960_CR79","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1471-4159.2010.06736.x","volume":"114","author":"MM Buchanan","year":"2010","unstructured":"Buchanan MM, Hutchinson M, Watkins LR, Yin H. Toll-like receptor 4 in CNS pathologies. J Neurochem. 2010;114(1):13\u201327.","journal-title":"J Neurochem"},{"key":"960_CR80","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.bbi.2014.06.203","volume":"42","author":"A Heiman","year":"2014","unstructured":"Heiman A, Pallottie A, Heary RF, Elkabes S. Toll-like receptors in central nervous system injury and disease: a focus on the spinal cord. Brain Behav Immun. 2014;42:232\u201345.","journal-title":"Brain Behav Immun"},{"issue":"2","key":"960_CR81","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.expneurol.2011.09.038","volume":"234","author":"L Nicotra","year":"2012","unstructured":"Nicotra L, Loram LC, Watkins LR, Hutchinson MR. Toll-like receptors in chronic pain. Exp Neurol. 2012;234(2):316\u201329.","journal-title":"Exp Neurol"},{"issue":"1","key":"960_CR82","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/j.1460-9568.2008.06321.x","volume":"28","author":"MR Hutchinson","year":"2008","unstructured":"Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008;28(1):20\u20139.","journal-title":"Eur J Neurosci"},{"issue":"12","key":"960_CR83","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.1016\/j.pain.2011.09.020","volume":"152","author":"CA Christianson","year":"2011","unstructured":"Christianson CA, Dumlao DS, Stokes JA, Dennis EA, Svensson CI, Corr M, et al. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain. 2011;152(12):2881\u201391.","journal-title":"Pain"},{"issue":"46","key":"960_CR84","doi-asserted-by":"publisher","first-page":"12565","DOI":"10.1523\/JNEUROSCI.3027-07.2007","volume":"27","author":"A Boivin","year":"2007","unstructured":"Boivin A, Pineau I, Barrette B, Filali M, Valli\u00e8res N, Rivest S, et al. Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury. J Neurosci. 2007;27(46):12565\u201376.","journal-title":"J Neurosci"},{"issue":"6","key":"960_CR85","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1002\/glia.23132","volume":"65","author":"JS Church","year":"2017","unstructured":"Church JS, Milich LM, Lerch JK, Popovich PG, McTigue DM. E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord. Glia. 2017;65(6):883\u201399.","journal-title":"Glia"},{"issue":"3","key":"960_CR86","first-page":"159","volume":"9","author":"A Rafiei","year":"2012","unstructured":"Rafiei A, Abedini M, Hosseini SH, Hosseini-Khah Z, Bazrafshan B, Tehrani M. Toll like receptor-4 896A\/G gene variation, a risk factor for migraine headaches. Iran J Immunol. 2012;9(3):159\u201367.","journal-title":"Iran J Immunol"},{"key":"960_CR87","doi-asserted-by":"crossref","first-page":"174480691875461","DOI":"10.1177\/1744806918754612","volume":"14","author":"M Su","year":"2018","unstructured":"Su M, Ran Y, He Z, Zhang M, Hu G, Tang W, et al. Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine. Mol Pain. 2018;14:1744806918754612.","journal-title":"Mol Pain"},{"key":"960_CR88","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.neuroscience.2020.10.019","volume":"451","author":"Q Gong","year":"2020","unstructured":"Gong Q, Lin Y, Lu Z, Xiao Z. Microglia-astrocyte cross talk through IL-18\/IL-18R signaling modulates migraine-like behavior in experimental models of migraine. Neuroscience. 2020;451:207\u201315.","journal-title":"Neuroscience"},{"key":"960_CR89","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.brainres.2017.03.011","volume":"1664","author":"J Wieseler","year":"2017","unstructured":"Wieseler J, Ellis A, McFadden A, Stone K, Brown K, Cady S, et al. Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators. Brain Res. 2017;1664:87\u201394.","journal-title":"Brain Res"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-022-00960-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-022-00960-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-022-00960-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T18:46:39Z","timestamp":1700937999000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-022-00960-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,20]]},"references-count":89,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["960"],"URL":"https:\/\/doi.org\/10.1186\/s13041-022-00960-5","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,20]]},"assertion":[{"value":"9 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 August 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"None of the authors report any conflicts of interests relevant to this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"73"}}