{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:05:29Z","timestamp":1789391129176,"version":"build-2803163510"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic low back pain (CLBP) is a leading cause of disability, yet radiographic degeneration correlates poorly with symptoms. This mini-review examines how immune-neural crosstalk may link intervertebral disc degeneration to pain initiation and persistence. Degenerated nucleus pulposus and annulus fibrosus cells develop inflammatory and catabolic phenotypes and release mediators that may promote neural and vascular ingrowth, sensitize nociceptors, and increase dorsal root ganglion neuron excitability. Sustained peripheral input may engage spinal glial pathways and contribute to central sensitization. Pain may persist through expectation, learning, affective processes, and altered central prediction even when peripheral inflammatory input is limited. These interactions are bidirectional: immune signaling may affect mood, cognition, sleep, and threat processing, whereas stress, pain-related beliefs, and social context may modify immune and neural responses through autonomic and neuroendocrine pathways. Vertebral endplate inflammation, sometimes reflected by Modic type I changes, may mark an immune-associated phenotype. Although mechanistic and preclinical evidence supports targets such as NGF and pro-inflammatory cytokines, clinical benefit has been inconsistent, potentially because of safety concerns, patient heterogeneity, insufficient target engagement, and trial-design limitations. We propose a systems framework integrating inflammatory biomarkers, endplate imaging, quantitative sensory testing, neuroimmune imaging, and contextual measures. This framework may help distinguish inflammation-dominant, peripherally sensitized, central-sensitization-associated, nociplastic (pain arising from altered nociception), and mixed profiles. Validation requires prospective longitudinal studies, biomarker-stratified cohorts, and adequately powered randomized controlled trials.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1926648","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:35:35Z","timestamp":1789389335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune-neural crosstalk in chronic low back pain: from intervertebral disc degeneration to pain sensitization"],"prefix":"10.3389","volume":"17","author":[{"given":"Jinjin","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyun","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Nursing, Beihai People\u2019s Hospital","place":["Beihai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaobin","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongwu","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00098-X","article-title":"Global, regional, and national burden of low back pain, 1990-2020, its attributable risk factors, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021","volume":"5","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30480-X","article-title":"What low back pain is and why we need to pay attention","volume":"391","author":"Hartvigsen","year":"2018","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A4173","article-title":"Systematic literature review of imaging features of spinal degeneration in asymptomatic populations","volume":"36","author":"Brinjikji","year":"2015","journal-title":"AJNR Am J Neuroradiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1093065","article-title":"Placebo-induced changes in fMRI in the anticipation and experience of pain","volume":"303","author":"Wager","year":"2004","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102693108","article-title":"Social rejection shares somatosensory representations with physical pain","volume":"108","author":"Kross","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/art.27444","article-title":"Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues","volume":"62","author":"Shamji","year":"2010","journal-title":"Arthritis Rheum"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110660","article-title":"The role of IL-1\u03b2 and TNF-\u03b1 in intervertebral disc degeneration","volume":"131","author":"Wang","year":"2020","journal-title":"BioMed Pharmacother"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v039a15","article-title":"Intervertebral disc and endplate cells response to IL-1\u03b2 inflammatory cell priming and identification of molecular targets of tissue degeneration","volume":"39","author":"De Luca","year":"2020","journal-title":"Eur Cell Mater"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202103631","article-title":"Single-cell transcriptome profiling reveals multicellular ecosystem of nucleus pulposus during degeneration progression","volume":"9","author":"Tu","year":"2022","journal-title":"Adv Sci (Weinh)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj3194","article-title":"Nuclear factor \u03baB overactivation in the intervertebral disc leads to macrophage recruitment and severe disc degeneration","volume":"10","author":"Burt","year":"2024","journal-title":"Sci Adv"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103339","article-title":"Chemerin facilitates intervertebral disc degeneration via TLR4 and CMKLR1 and activation of NF-kB signaling pathway","volume":"12","author":"Hu","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/ar.23059","article-title":"Enhanced NLRP3, caspase-1, and IL-1\u03b2 levels in degenerate human intervertebral disc and their association with the grades of disc degeneration","volume":"298","author":"Chen","year":"2015","journal-title":"Anat Rec (Hoboken)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.03.161","article-title":"Propionibacterium acnes induces intervertebral disc degeneration by promoting nucleus pulposus cell pyroptosis via NLRP3-dependent pathway","volume":"526","author":"He","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.111992","article-title":"Research on the role and mechanism of IL-17 in intervertebral disc degeneration","volume":"132","author":"Peng","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/art.34456","article-title":"Intervertebral disc and macrophage interaction induces mechanical hyperalgesia and cytokine production in a herniated disc model in rats","volume":"64","author":"Takada","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)02135-1","article-title":"Nerve ingrowth into diseased intervertebral disc in chronic back pain","volume":"350","author":"Freemont","year":"1997","journal-title":"Lancet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-014-0416-1","article-title":"Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration","volume":"16","author":"Binch","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047735","article-title":"Degenerate human nucleus pulposus cells promote neurite outgrowth in neural cells","volume":"7","author":"Richardson","year":"2012","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2015.11.019","article-title":"Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo","volume":"16","author":"Lai","year":"2016","journal-title":"Spine J"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000000334","article-title":"ISSLS Prize winner: Increased innervation and sensory nervous system plasticity in a mouse model of low back pain due to intervertebral disc degeneration","volume":"39","author":"Miyagi","year":"2014","journal-title":"Spine (Phila Pa 1976)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/jor.24682","article-title":"Degenerative IVD conditioned media and acidic pH sensitize sensory neurons to cyclic tensile strain","volume":"39","author":"Stover","year":"2021","journal-title":"J Orthop Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2014.01.492","article-title":"Contribution of chemokine CCL2\/CCR2 signaling in the dorsal root ganglion and spinal cord to the maintenance of neuropathic pain in a rat model of lumbar disc herniation","volume":"15","author":"Zhu","year":"2014","journal-title":"J Pain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s12264-017-0106-5","article-title":"Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms","volume":"34","author":"Xie","year":"2018","journal-title":"Neurosci Bull"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00348.2020","article-title":"Spinal cord fractalkine (CX3CL1) signaling is critical for neuronal sensitization in experimental nonspecific, myofascial low back pain","volume":"125","author":"Sessler","year":"2021","journal-title":"J Neurophysiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature04223","article-title":"BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain","volume":"438","author":"Coull","year":"2005","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/glia.22379","article-title":"Microglia and intractable chronic pain","volume":"61","author":"Tsuda","year":"2013","journal-title":"Glia"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.11.009","article-title":"Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain","volume":"100","author":"Chen","year":"2018","journal-title":"Neuron"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000002130","article-title":"Neuroinflammation and central sensitization in chronic and widespread pain","volume":"129","author":"Ji","year":"2018","journal-title":"Anesthesiology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1650-20.2020","article-title":"The neuroimmunology of chronic pain: from rodents to humans","volume":"41","author":"Grace","year":"2021","journal-title":"J Neurosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu377","article-title":"Evidence for brain glial activation in chronic pain patients","volume":"138","author":"Loggia","year":"2015","journal-title":"Brain"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1097\/AJP.0000000000000755","article-title":"A subgroup of chronic low back pain patients with central sensitization","volume":"35","author":"Aoyagi","year":"2019","journal-title":"Clin J Pain"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.1140","article-title":"Assessment and manifestation of central sensitisation across different chronic pain conditions","volume":"22","author":"Arendt-Nielsen","year":"2018","journal-title":"Eur J Pain"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00680.2016","article-title":"Prevention and reversal of latent sensitization of dorsal horn neurons by glial blockers in a model of low back pain in male rats","volume":"118","author":"Zhang","year":"2017","journal-title":"J Neurophysiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1001\/jamapsychiatry.2021.2669","article-title":"Effect of pain reprocessing therapy vs placebo and usual care for patients with chronic back pain: A randomized clinical trial","volume":"79","author":"Ashar","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.12.009","article-title":"Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood","volume":"24","author":"Eisenberger","year":"2010","journal-title":"Brain Behav Immun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S147735","article-title":"The impact of anxiety and catastrophizing on interleukin-6 responses to acute painful stress","volume":"11","author":"Lazaridou","year":"2018","journal-title":"J Pain Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-016-4459-7","article-title":"Pathobiology of modic changes","volume":"25","author":"Dudli","year":"2016","journal-title":"Eur Spine J"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/01.brs.0000215027.87102.7c","article-title":"Tumor necrosis factor-immunoreactive cells and PGP 9.5-immunoreactive nerve fibers in vertebral endplates of patients with discogenic low back pain and Modic Type 1 or Type 2 changes on MRI","volume":"31","author":"Ohtori","year":"2006","journal-title":"Spine (Phila Pa 1976)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-017-4955-4","article-title":"ISSLS PRIZE IN BASIC SCIENCE 2017: Intervertebral disc\/bone marrow cross-talk with Modic changes","volume":"26","author":"Dudli","year":"2017","journal-title":"Eur Spine J"},{"key":"B41","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41598-021-04189-5","article-title":"Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement","volume":"12","author":"Vigeland","year":"2022","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2021-001726","article-title":"Macrophage migration inhibitory factor: a potential biomarker for chronic low back pain in patients with Modic changes","volume":"7","author":"Gjefsen","year":"2021","journal-title":"RMD Open"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2024.04.003","article-title":"Association between vertebral endplate defects and patient-reported symptoms: an immunohistochemical study investigating the COX-2\/PGE-2\/EP-4 axis","volume":"24","author":"Chen","year":"2024","journal-title":"Spine J"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1177\/21925682221143332","article-title":"Modic changes of the cervical and lumbar spine and their effect on neck and back pain: A systematic review and meta-analysis","volume":"13","author":"Lambrechts","year":"2023","journal-title":"Global Spine J"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002911","article-title":"Identifying chronic low back pain phenotypic domains and characteristics accounting for individual variation: a systematic review","volume":"164","author":"Hassan","year":"2023","journal-title":"Pain"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/10538127251357279","article-title":"Biopsychosocial phenotyping of patients with chronic low back pain using the pain and disability drivers management model: a retrospective cohort study","volume":"39","author":"Le Cam","year":"2026","journal-title":"J Back Musculoskelet Rehabil"},{"key":"B47","doi-asserted-by":"publisher","first-page":"59","DOI":"10.21037\/apm-2026-1-0026","article-title":"Operational phenotyping for chronic low back pain: a narrative review and methodology for developing routing and escalation pathways across spine care","volume":"15","author":"Lewandrowski","year":"2026","journal-title":"Ann Palliat Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00324-7","article-title":"Nociceptive, neuropathic, or nociplastic low back pain? The low back pain phenotyping (BACPAP) consortium's international and multidisciplinary consensus recommendations","volume":"6","author":"Nijs","year":"2024","journal-title":"Lancet Rheumatol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001928","article-title":"Tanezumab for chronic low back pain: a randomized, double-blind, placebo- and active-controlled, phase 3 study of efficacy and safety","volume":"161","author":"Markman","year":"2020","journal-title":"Pain"},{"key":"B50","unstructured":"Raylumis (Tanezumab): Refusal of Marketing Authorisation\n          \n          \n          \n          2022"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1097\/01.brs.0000435140.61593.4c","article-title":"Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation","volume":"38","author":"Freeman","year":"2013","journal-title":"Spine (Phila Pa 1976)"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/art.27499","article-title":"Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial","volume":"62","author":"Genevay","year":"2010","journal-title":"Arthritis Rheum"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD009790.pub2","article-title":"Exercise therapy for chronic low back pain","volume":"9","author":"Hayden","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"key":"B54","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1186\/s12891-024-07289-1","article-title":"The changes of blood-based inflammatory biomarkers after non-pharmacologic interventions for chronic low back pain: a systematic review","volume":"25","author":"Puerto Valencia","year":"2024","journal-title":"BMC Musculoskelet Disord"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.2167","article-title":"Are biomarkers associated with sensitivity to physical activity","volume":"28","author":"Flegg","year":"2024","journal-title":"Eur J Pain"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1926648\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:35:38Z","timestamp":1789389338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1926648\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2026.1926648"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1926648","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"article-number":"1926648"}}