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Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Anti-inflammatory T-cell shift in neuropathic pain

Authors: Benjamin Luchting, Banafscheh Rachinger-Adam, Jens Heyn, Ludwig Christian Hinske, Simone Kreth, Shahnaz Christina Azad

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

The classification of pain into nociceptive and neuropathic pain is based on characteristic symptoms and different pathophysiological mechanisms. In a recent investigation, we found a disrupted TH17/Treg balance in patients suffering from chronic unspecific low back pain (CLBP). These patients did not show any signs of neuropathy. There is evidence for a considerable impact of the immune system also in neuropathic pain. However, the role of the adaptive immune system is still unclear. In the present study, we investigated systemic T-cell subset responses and T-cell related cytokine profiles in patients with chronic neuropathic pain.

Methods

We analyzed T-cell subsets, mRNA expression and T-cell-related cytokine profiles in 26 patients suffering from neuropathic pain in comparison to 26 healthy controls. Using multicolor flow cytometry (FACS), we quantified the number of T helper cells 1 (TH1), TH2, TH17 and regulatory T-cells (Tregs). Forkhead-Box-Protein 3 (FoxP3), Transforming growth factor-β (TGF-β) and RAR-related orphan receptor-γT (ROR-γT) mRNA expression was determined by quantitative real-time PCR (qPCR) and levels of pain-related cytokines were measured by Human Cytokine Multiplex Immunoassay (Macrophage inflammatory protein-1α (MIP-1α), Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), Interleukin (IL) -4, IL-6, IL-10, IL-17, and IL-23).

Results

We found a TH17/Treg imbalance with significantly increased anti-inflammatory Tregs and decreased pro-inflammatory TH17 cells in patients with neuropathic pain as compared to healthy controls. These results were confirmed on mRNA level: Treg-related FoxP3 and TGF-β mRNA expression was elevated, whereas expression of TH17-related RORγT was reduced. Cytokine analyses revealed only marginal changes.

Conclusions

Our investigation revealed a clear shift of T-cell subsets towards anti-inflammation in patients with neuropathic pain. Interestingly, this is quite similar to our previous findings in CLBP patients, but even more pronounced. Therefore, it remains to be elucidated in future investigations whether the immune changes represent an underlying pathophysiological mechanism or an epiphenomenon induced by ongoing pain and stress.

German Clinical Trial Register (DRKS)

Trial registration number: DRKS00005954
Appendix
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Literature
1.
go back to reference Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–5.PubMedCrossRef Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–5.PubMedCrossRef
2.
go back to reference Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ. 2014;348:f7656.PubMedCrossRef Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ. 2014;348:f7656.PubMedCrossRef
3.
go back to reference Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol. 2010;229(1–2):26–50.PubMedCrossRef Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol. 2010;229(1–2):26–50.PubMedCrossRef
4.
go back to reference Tian L, Ma L, Kaarela T, Li Z. Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J Neuroinflammation. 2012;9:155.PubMedCentralPubMedCrossRef Tian L, Ma L, Kaarela T, Li Z. Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J Neuroinflammation. 2012;9:155.PubMedCentralPubMedCrossRef
5.
go back to reference Iwatsuki K, Arai T, Ota H, Kato S, Natsume T, Kurimoto S, et al. Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain. PLoS One. 2013;8(2):e57721.PubMedCentralPubMedCrossRef Iwatsuki K, Arai T, Ota H, Kato S, Natsume T, Kurimoto S, et al. Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain. PLoS One. 2013;8(2):e57721.PubMedCentralPubMedCrossRef
6.
go back to reference Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A, et al. Inhibition of IL-6 signaling: a novel therapeutic approach to treating spinal cord injury pain. Pain. 2013;154(7):1115–28.PubMedCrossRef Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A, et al. Inhibition of IL-6 signaling: a novel therapeutic approach to treating spinal cord injury pain. Pain. 2013;154(7):1115–28.PubMedCrossRef
7.
go back to reference Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation. Pain. 2010;149(2):305–15.PubMedCrossRef Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation. Pain. 2010;149(2):305–15.PubMedCrossRef
8.
go back to reference Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011;12(3):370–83.PubMedCrossRef Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011;12(3):370–83.PubMedCrossRef
10.
go back to reference Cunha FQ, Poole S, Lorenzetti BB, Veiga FH, Ferreira SH. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-4. Br J Pharmacol. 1999;126(1):45–50.PubMedCrossRef Cunha FQ, Poole S, Lorenzetti BB, Veiga FH, Ferreira SH. Cytokine-mediated inflammatory hyperalgesia limited by interleukin-4. Br J Pharmacol. 1999;126(1):45–50.PubMedCrossRef
11.
go back to reference Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP. Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol. 2001;168(1):144–54.PubMedCrossRef Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP. Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol. 2001;168(1):144–54.PubMedCrossRef
12.
go back to reference Echeverry S, Shi XQ, Haw A, Liu H, Zhang ZW, Zhang J. Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain. 2009;5:16.PubMedCentralPubMedCrossRef Echeverry S, Shi XQ, Haw A, Liu H, Zhang ZW, Zhang J. Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects. Mol Pain. 2009;5:16.PubMedCentralPubMedCrossRef
13.
go back to reference Perkins NM, Tracey DJ. Hyperalgesia due to nerve injury: role of neutrophils. Neuroscience. 2000;101(3):745–57.PubMedCrossRef Perkins NM, Tracey DJ. Hyperalgesia due to nerve injury: role of neutrophils. Neuroscience. 2000;101(3):745–57.PubMedCrossRef
14.
go back to reference Liu HH, Xia XY, Wu YM, Pan LJ, Jin BF, Shang XJ, et al. Detection of peripheral blood Th1/Th2 cell ratio in patients with chronic abacterial prostatitis/chronic pelvic pain syndrome. Zhonghua Nan Ke Xue. 2006;12(4):330–2. 336.PubMed Liu HH, Xia XY, Wu YM, Pan LJ, Jin BF, Shang XJ, et al. Detection of peripheral blood Th1/Th2 cell ratio in patients with chronic abacterial prostatitis/chronic pelvic pain syndrome. Zhonghua Nan Ke Xue. 2006;12(4):330–2. 336.PubMed
15.
go back to reference Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M. Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain. 2006;22(3):235–9.PubMedCrossRef Schinkel C, Gaertner A, Zaspel J, Zedler S, Faist E, Schuermann M. Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain. 2006;22(3):235–9.PubMedCrossRef
16.
go back to reference Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol. 2006;200(2):480–5.PubMedCrossRef Kleinschnitz C, Hofstetter HH, Meuth SG, Braeuninger S, Sommer C, Stoll G. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol. 2006;200(2):480–5.PubMedCrossRef
17.
go back to reference Austin PJ, Kim CF, Perera CJ, Moalem-Taylor G. Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis. Pain. 2012;153(9):1916–31.PubMedCrossRef Austin PJ, Kim CF, Perera CJ, Moalem-Taylor G. Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis. Pain. 2012;153(9):1916–31.PubMedCrossRef
18.
go back to reference Xing Q, Hu D, Shi F, Chen F. Role of regulatory T cells in patients with acute herpes zoster and relationship to postherpetic neuralgia. Arch Dermatol Res. 2013;305(8):715–22.PubMedCrossRef Xing Q, Hu D, Shi F, Chen F. Role of regulatory T cells in patients with acute herpes zoster and relationship to postherpetic neuralgia. Arch Dermatol Res. 2013;305(8):715–22.PubMedCrossRef
19.
go back to reference Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.PubMedCrossRef Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.PubMedCrossRef
20.
go back to reference Luchting B, Rachinger-Adam B, Zeitler J, Egenberger L, Mohnle P, Kreth S, et al. Disrupted TH17/Treg balance in patients with chronic low back pain. PLoS One. 2014;9(8):e104883.PubMedCentralPubMedCrossRef Luchting B, Rachinger-Adam B, Zeitler J, Egenberger L, Mohnle P, Kreth S, et al. Disrupted TH17/Treg balance in patients with chronic low back pain. PLoS One. 2014;9(8):e104883.PubMedCentralPubMedCrossRef
21.
go back to reference Freynhagen R, Baron R, Gockel U. Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911–20.PubMedCrossRef Freynhagen R, Baron R, Gockel U. Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911–20.PubMedCrossRef
22.
go back to reference Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150(3):439–50.PubMedCrossRef Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain. 2010;150(3):439–50.PubMedCrossRef
23.
go back to reference Gauter-Fleckenstein B, Kaviani R, Weiss C, Burges A, Korell M, Anthuber C, et al. Perioperative patient management. Evaluation of subjective stress and demands of patients undergoing elective gynaecological surgery. Anaesthesist. 2007;56(6):562–70.PubMedCrossRef Gauter-Fleckenstein B, Kaviani R, Weiss C, Burges A, Korell M, Anthuber C, et al. Perioperative patient management. Evaluation of subjective stress and demands of patients undergoing elective gynaecological surgery. Anaesthesist. 2007;56(6):562–70.PubMedCrossRef
24.
go back to reference Chowdhury F, Williams A, Johnson P. Validation and comparison of two multiplex technologies, Luminex and Mesoscale Discovery, for human cytokine profiling. J Immunol Methods. 2009;340(1):55–64.PubMedCrossRef Chowdhury F, Williams A, Johnson P. Validation and comparison of two multiplex technologies, Luminex and Mesoscale Discovery, for human cytokine profiling. J Immunol Methods. 2009;340(1):55–64.PubMedCrossRef
25.
go back to reference Venet F, Malcus C, Ferry T, Poitevin F, Monneret G. Percentage of regulatory T cells CD4 + CD25 + CD127- in HIV-infected patients is not reduced after cryopreservation. J Immunol Methods. 2010;357(1–2):55–8.PubMedCrossRef Venet F, Malcus C, Ferry T, Poitevin F, Monneret G. Percentage of regulatory T cells CD4 + CD25 + CD127- in HIV-infected patients is not reduced after cryopreservation. J Immunol Methods. 2010;357(1–2):55–8.PubMedCrossRef
26.
go back to reference Ledderose C, Heyn J, Limbeck E, Kreth S. Selection of reliable reference genes for quantitative real-time PCR in human T cells and neutrophils. BMC Res Notes. 2011;4:427.PubMedCentralPubMedCrossRef Ledderose C, Heyn J, Limbeck E, Kreth S. Selection of reliable reference genes for quantitative real-time PCR in human T cells and neutrophils. BMC Res Notes. 2011;4:427.PubMedCentralPubMedCrossRef
27.
go back to reference Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother. 2012;61(2):283–8.PubMedCrossRef Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother. 2012;61(2):283–8.PubMedCrossRef
28.
go back to reference Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer. 2012;75(1):95–101.PubMedCrossRef Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, et al. Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer. 2012;75(1):95–101.PubMedCrossRef
29.
go back to reference Toth C, Lander J, Wiebe S. The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med. 2009;10(5):918–29.PubMedCrossRef Toth C, Lander J, Wiebe S. The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med. 2009;10(5):918–29.PubMedCrossRef
30.
go back to reference Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun. 2007;21(5):599–616.PubMedCrossRef Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun. 2007;21(5):599–616.PubMedCrossRef
31.
go back to reference Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009;29(46):14415–22.PubMedCentralPubMedCrossRef Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009;29(46):14415–22.PubMedCentralPubMedCrossRef
32.
go back to reference Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.PubMedCrossRef Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500.PubMedCrossRef
33.
go back to reference Lenz M, Uceyler N, Frettloh J, Hoffken O, Krumova EK, Lissek S, et al. Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. Pain. 2013;154(10):2142–9.PubMedCrossRef Lenz M, Uceyler N, Frettloh J, Hoffken O, Krumova EK, Lissek S, et al. Local cytokine changes in complex regional pain syndrome type I (CRPS I) resolve after 6 months. Pain. 2013;154(10):2142–9.PubMedCrossRef
34.
go back to reference Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130(4):601–30.PubMedCentralPubMedCrossRef Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130(4):601–30.PubMedCentralPubMedCrossRef
35.
go back to reference Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008;16(3):19–33.PubMedCentralPubMed Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008;16(3):19–33.PubMedCentralPubMed
37.
go back to reference Hong M, Zheng J, Ding ZY, Chen JH, Yu L, Niu Y, et al. Imbalance between Th17 and Treg cells may play an important role in the development of chronic unpredictable mild stress-induced depression in mice. Neuroimmunomodulation. 2013;20(1):39–50.PubMedCrossRef Hong M, Zheng J, Ding ZY, Chen JH, Yu L, Niu Y, et al. Imbalance between Th17 and Treg cells may play an important role in the development of chronic unpredictable mild stress-induced depression in mice. Neuroimmunomodulation. 2013;20(1):39–50.PubMedCrossRef
38.
go back to reference Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5(3):243–51.PubMedCrossRef Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5(3):243–51.PubMedCrossRef
Metadata
Title
Anti-inflammatory T-cell shift in neuropathic pain
Authors
Benjamin Luchting
Banafscheh Rachinger-Adam
Jens Heyn
Ludwig Christian Hinske
Simone Kreth
Shahnaz Christina Azad
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-014-0225-0

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