Severity of intervertebral disc herniation regulates cytokine and chemokine levels in patients with chronic radicular back pain

H E Jacobsen, A N Khan, M E Levine, C G Filippi, N O Chahine, H E Jacobsen, A N Khan, M E Levine, C G Filippi, N O Chahine

Abstract

Objective: The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects.

Design: Cytokine levels from lumbar DH subjects (N = 78) were compared to control subjects (N = 57) accounting for effects of DH, age, body mass index (BMI) and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery.

Results: Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of macrophage migration inhibitory factor (MIF) decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery.

Conclusions: This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

Keywords: Herniated disc; Inflammation; Intervertebral disc; MRI severity; Pain.

Conflict of interest statement

Conflict of Interest

The authors have declared that no conflict of interest exists

Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1.
Figure 1.
Radiological analysis of herniation severity. (a,b) moderate-sized herniation showing (a) T2-weighted MRI and (b) measurement of disc herniation (dashed line) and the central canal diameter (solid line) in the anterior to posterior dimension. (c,d) Large (i.e. severe) central disc herniation showing measurements of disc herniation (dashed) and the central spinal canal (solid line) in the anterior to posterior dimensions. (e) Axial T2 weighted image of a small (i.e. mild) central herniation with ventral effacement of the thecal sac but no associated nerve root compression. (f) Right subarticular herniation with ventral effacement of the thecal sac and compression of the traversing nerve root.
Figure 2.
Figure 2.
Serum levels of (a) HMGB1, (b) PDGFbb, and (c) IL-9 in DH subjects as function of DH severity. #pρ) and p value for significant correlations observed % intrusion (of herniation) and serum levels of (d) HMGB-1 (N=78), (e) PDGF-bb (N=78), and (f) Pain (VAS; N=34). (g) Spearman correlation between VAS and MMP-1 levels (N=34). Each point on scatter plot represents one subject, and line represents the correlation fit.
Figure 3.
Figure 3.
Effects of DH severity in chronic (a-h) and acute (a’-h’) subjects. (a, a’) VAS scores across severity groups. (b,b’) Spearman correlation between VAS and (b) Eotaxin or (b’) MMP-1 (ρ: Spearman correlation coefficient). Serum levels of (c,c’) HMGB1, (d,d’) PDGFbb, (e,e’) MMP-1, (f,f’) IL-9, (g,g’) Eotaxin, and (h,h’) RANTES in chronic and acute subjects, respectively. Bar graph are indicative of mean and standard deviation. * p<0.05 vs. Mild in multiple group comparison based on post-hoc test.
Figure 4.
Figure 4.
(a) Volcano plot of serum cytokine levels post surgery vs. pre-surgery. Each triangle represents fold change (Post/Pre) in cytokine level (x-axis) and p-value (y-axis). Fold change=1 is indicated as ‘No effect’ and significance was set at p=0.05. Serum levels of (b) MF decreased post surgery, while levels of (c) CCL11, (d) CCL3, (e) CXCL1, and (f) CXCL10 significantly increased post surgery. In (b) to (f) scatter plot indicate individual patient levels pre- and post-surgery, with bar graph indicative of mean and standard deviation.

References

    1. Gore M, Sadosky A, Stacey BR, Tai KS, Leslie D. The burden of chronic low back pain: clinical comorbidities, treatment patterns, and health care costs in usual care settings. Spine (Phila Pa 1976) 2012. May 15;37(11):E668–77.
    1. Tsarouhas A, Soufla G, Katonis P, Pasku D, Vakis A, Spandidos DA. Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation. Eur Spine J. 2011. May;20(5):781–90.
    1. Zigouris A, Batistatou A, Alexiou GA, Pachatouridis D, Mihos E, Drosos D, et al. Correlation of matrix metalloproteinases-1 and -3 with patient age and grade of lumbar disc herniation. J Neurosurg Spine. 2011. February;14(2):268–72.
    1. Omarker K, Myers RR. Pathogenesis of sciatic pain: role of herniated nucleus pulposus and deformation of spinal nerve root and dorsal root ganglion. Pain. 1998. November;78(2):99–105.
    1. Rydevik B, Brown MD, Lundborg G. Pathoanatomy and pathophysiology of nerve root compression. Spine (Phila Pa 1976). 1984. January-Feb;9(1):7–15.
    1. Doita M, Kanatani T, Harada T, Mizuno K. Immunohistologic study of the ruptured intervertebral disc of the lumbar spine. Spine (Phila Pa 1976). 1996. January 15;21(2):235–41.
    1. Gronblad M, Virri J, Tolonen J, Seitsalo S, Kaapa E, Kankare J, et al. A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine (Phila Pa 1976). 1994. December 15;19(24):2744–51.
    1. Ma XL, Tian P, Wang T, Ma JX. A study of the relationship between type of lumbar disc herniation, straight leg raising test and peripheral T lymphocytes. Orthop Surg. 2010. February;2(1):52–7.
    1. Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T. Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (Phila Pa 1976). 1996. January 15;21(2):218–24.
    1. de Goeij M, van Eijk LT, Vanelderen P, Wilder-Smith OH, Vissers KC, van der Hoeven JG, et al. Systemic inflammation decreases pain threshold in humans in vivo. PLoS One. 2013;8(12):e84159.
    1. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009. October 16;139(2):267–84.
    1. Otoshi K, Kikuchi S, Kato K, Sekiguchi M, Konno S. Anti-HMGB1 neutralization antibody improves pain-related behavior induced by application of autologous nucleus pulposus onto nerve roots in rats. Spine (Phila Pa 1976). 2011. May 15;36(11):E692–8.
    1. Sasaki N, Sekiguchi M, Shishido H, Kikuchi S, Yabuki S, Konno S. A comparison of pain-related behavior following local application of nucleus pulposus and/or mechanical compression on the dorsal root ganglion. Fukushima J Med Sci. 2011;57(2):46–53.
    1. Yamashita M, Ohtori S, Koshi T, Inoue G, Yamauchi K, Suzuki M, et al. Tumor necrosis factor-alpha in the nucleus pulposus mediates radicular pain, but not increase of inflammatory peptide, associated with nerve damage in mice. Spine (Phila Pa 1976). 2008. August 1;33(17):1836–42.
    1. Suzuki M, Inoue G, Gemba T, Watanabe T, Ito T, Koshi T, et al. Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model. Eur Spine J. 2009. July;18(7):1001–7.
    1. Brisby H, Olmarker K, Larsson K, Nutu M, Rydevik B. Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica. Eur Spine J. 2002. February;11(1):62–6.
    1. Park MS, Lee HM, Hahn SB, Moon SH, Kim YT, Lee CS, et al. The association of the activation-inducible tumor necrosis factor receptor and ligand with lumbar disc herniation. Yonsei Med J. 2007. October 31;48(5):839–46.
    1. Cheng L, Fan W, Liu B, Wang X, Nie L. Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity. Injury. 2013. December;44(12):1805–10.
    1. Kraychete DC, Sakata RK, Issy AM, Bacellar O, Santos-Jesus R, Carvalho EM. Serum cytokine levels in patients with chronic low back pain due to herniated disc: analytical cross-sectional study. Sao Paulo Med J. 2010;128(5):259–62.
    1. Grad S, Bow C, Karppinen J, Luk KD, Cheung KM, Alini M, et al. Systemic blood plasma CCL5 and CXCL6: Potential biomarkers for human lumbar disc degeneration. Eur Cell Mater. 2016. January;31:1–10.
    1. Pedersen LM, Schistad E, Jacobsen LM, Roe C, Gjerstad J. Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: A 12-month prospective study. Brain Behav Immun. 2015. May;46:132–6.
    1. Moen A, Lind AL, Thulin M, Kamali-Moghaddam M, Roe C, Gjerstad J, et al. Inflammatory Serum Protein Profiling of Patients with Lumbar Radicular Pain One Year after Disc Herniation. Int J Inflam. 2016;2016:3874964.
    1. Rajasekaran S, Tangavel C, K S SVA, Soundararajan DCR, Nayagam SM, Matchado MS, et al. Inflammaging determines health and disease in lumbar discs-evidence from differing proteomic signatures of healthy, aging, and degenerating discs. Spine J. 2020. 01;20(1):48–59.
    1. Hashem LE, Roffey DM, Alfasi AM, Papineau GD, Wai DC, Phan P, et al. Exploration of the Inter-Relationships Between Obesity, Physical Inactivity, Inflammation, and Low Back Pain. Spine (Phila Pa 1976). 2018. 09;43(17):1218–24.
    1. Weber KT, Alipui DO, Sison CP, Bloom O, Quraishi S, Overby MC, et al. Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases. Arthritis Res Ther. 2016. January 7;18:3.
    1. Weber KT, Satoh S, Alipui DO, Virojanapa J, Levine M, Sison C, et al. Exploratory study for identifying systemic biomarkers that correlate with pain response in patients with intervertebral disc disorders. Immunol Res. 2015. December;63(1-3):170–80.
    1. Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976). 2001. September;26(17):1873–8.
    1. Janelidze S, Ventorp F, Erhardt S, Hansson O, Minthon L, Flax J, et al. Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters. Psychoneuroendocrinology. 2013. June;38(6):853–62.
    1. Rahyussalim AJ, Zufar MLL, Kurniawati T. Significance of the Association between Disc Degeneration Changes on Imaging and Low Back Pain: A Review Article. Asian Spine J. 2020. April;14(2):245–57.
    1. DeVine J, Norvell DC, Ecker E, Fourney DR, Vaccaro A, Wang J, et al. Evaluating the correlation and responsiveness of patient-reported pain with function and quality-of-life outcomes after spine surgery. Spine (Phila Pa 1976). 2011. October 1;36(21 Suppl):S69–74.
    1. Fardon DF, Williams AL, Dohring EJ, Murtagh FR, Gabriel Rothman SL, Sze GK. Lumbar disc nomenclature: version 2.0: Recommendations of the combined task forces of the North American Spine Society, the American Society of Spine Radiology and the American Society of Neuroradiology. Spine J. 2014. November 1;14(11):2525–45.
    1. Shah B, Levine M, Alipui DO, Weber KT, Chahine NO. 2017. Orthopedic Reserach Society; San Diego, CA: High Mobility Group Box-1 Promotes Pro-inflammatory Signaling in Human Nucleus Pulposus Cells via Toll-Like Receptor 4. p. 49.
    1. Gruber HE, Hoelscher GL, Bethea S, Ingram J, Cox M, Hanley EN. High-mobility group box-1 gene, a potent proinflammatory mediators, is upregulated in more degenerated human discs in vivo and its receptor upregulated by TNF-α exposure in vitro. Exp Mol Pathol. 2015. June;98(3):427–30.
    1. Shah BS, Burt KG, Jacobsen T, Fernandes TD, Alipui DO, Weber KT, et al. High mobility group box-1 induces pro-inflammatory signaling in human nucleus pulposus cells via toll-like receptor 4-dependent pathway. J Orthop Res. 2019. January;37(1):220–31.
    1. Maeda T, Ozaki M, Kobayashi Y, Kiguchi N, Kishioka S. HMGB1 as a potential therapeutic target for neuropathic pain. J Pharmacol Sci. 2013;123(4):301–5.
    1. Presciutti SM, Paglia DN, Karukonda T, Soung dY, Guzzo R, Drissi H, et al. PDGF-BB inhibits intervertebral disc cell apoptosis in vitro. J Orthop Res. 2014. September;32(9):1181–8.
    1. Gruber HE, Norton HJ, Hanley EN. Anti-apoptotic effects of IGF-1 and PDGF on human intervertebral disc cells in vitro. Spine (Phila Pa 1976). 2000. September;25(17):2153–7.
    1. Pratsinis H, Constantinou V, Pavlakis K, Sapkas G, Kletsas D. Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. J Orthop Res. 2012. June;30(6):958–64.
    1. Paglia DN, Singh H, Karukonda T, Drissi H, Moss IL. PDGF-BB Delays Degeneration of the Intervertebral Discs in a Rabbit Preclinical Model. Spine (Phila Pa 1976). 2016. April;41(8):E449–58.
    1. Geiss A, Larsson K, Rydevik B, Takahashi I, Olmarker K. Autoimmune properties of nucleus pulposus: an experimental study in pigs. Spine (Phila Pa 1976). 2007. January 15;32(2):168–73.
    1. Zhang Y, Zhao Y, Li J, Wang S, Liu Y, Nie L, et al. Interleukin-9 Promotes TNF-α and PGE2 Release in Human Degenerated Intervertebral Disc Tissues. Spine (Phila Pa 1976). 2016. November;41(21):1631–40.
    1. Polacchini A, Girardi D, Falco A, Zanotta N, Comar M, De Carlo NA, et al. Distinct CCL2, CCL5, CCL11, CCL27, IL-17, IL-6, BDNF serum profiles correlate to different job-stress outcomes. Neurobiol Stress. 2018. February;8:82–91.
    1. Liang H, Yang X, Liu C, Sun Z, Wang X. Effect of NF-kB signaling pathway on the expression of MIF, TNF-alpha, IL-6 in the regulation of intervertebral disc degeneration. J Musculoskelet Neuronal Interact. 2018. December 1;18(4):551–6.
    1. Biancotto A, Wank A, Perl S, Cook W, Olnes MJ, Dagur PK, et al. Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. PLoS One. 2013;8(12):e76091.
    1. Raman D, Sobolik-Delmaire T, Richmond A. Chemokines in health and disease. Exp Cell Res. 2011. March 10;317(5):575–89.

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