A Review of the Role of Lymphocytes in Chronic Neuropathic Pain: A Clinical Perspective

Main Article Content

Connail McCrory DA Galvin DA Galvin

Abstract

Chronic neuropathic pain is one of the most common morbidities in the developed world. It has a lifetime incidence of 80% with females being affected more than males. Chronic neuropathic pain pathogenesis and its associated “sickness syndrome” has been poorly understood but recent research has shown a neuroimmune basis. Many studies performed to date have been pre-clinical or animal-based with a lack of human studies in chronic neuropathic pain.


Background: We performed a review of literature with emphasis on clinical and human studies. The numbers of such studies are low due to limitations with ethical approval, recruitment and heterogeneity of humans. We aimed to investigate the most recent studies as well as important seminal research in this area.


Methods: Literature search was performed using Stella search engine, Pubmed and National Library of Medicine search engines. Pre-clinical, animal and human studies were included.


Conclusion: The immune system, in particular the adaptive immune system, regulates the initiation, progression and resolution of chronic neuropathic pain in humans. The exact “switch” which mediates initiation, upregulation and downregulation of the components of the immune system is not known. Further research in this area is needed but the challenge of recruiting patients for CNP studies remains. Study sample sizes tend to be small. However, clinically relevant findings although small can offer important information to further our understanding of CNP.

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How to Cite
MCCRORY, Connail; GALVIN, DA; GALVIN, DA. A Review of the Role of Lymphocytes in Chronic Neuropathic Pain: A Clinical Perspective. Medical Research Archives, [S.l.], v. 11, n. 2, feb. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3596>. Date accessed: 25 apr. 2024. doi: https://doi.org/10.18103/mra.v11i2.3596.
Section
Review Articles

References

1. Headland SE, Norling LV. The resolution of inflammation: Principles and challenges. Semin Immunol. 2015;27(3):149-160. doi:10.1016/j.smim.2015.03.014
2. Rice ASC, Smith BH, Blyth FM. Pain and the global burden of disease. Pain. 2016;157(4):791-796. doi:10.1097/j.pain.0000000000000454
3. International Association for the Study of Pain. IASP Taxonomy. Pain terms. Neuropathic pain. Updated 2017 Dec 14. www.iasp-pain.org/Taxonomy#Neuropathicpain [cited 2018 May 1]
4. Attal N, Lanteri-Minet M, Laurent B, Fermanian J, Bouhassira D. The specific disease burden of neuropathic pain: results of a French nationwide survey. Pain. 2011 Dec;152(12):2836-2843. DOI: 10.1016/j.pain.2011.09.014. PMID: 22019149.
5. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nature reviews. Immunology. 2014 Apr;14(4):217-231. DOI: 10.1038/nri3621. PMID: 24577438; PMCID: PMC5525062.
6. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. doi:10.1016/S1474-4422(14)70251-0
7. Deer TR, Grider JS, Lamer TJ, et al. A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain [published correction appears in Pain Med. 2021 Feb 4;22(1):236]. Pain Med. 2020;21(7):1421-1432. doi:10.1093/pm/pnz353
8. Kumar K, Taylor RS, Jacques L, et al. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain. 2007;132(1-2):179-188. doi:10.1016/j.pain.2007.07.028
9. Albrecht DS, Ahmed SU, Kettner NW, et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain. 2018;159(5):968-977. doi:10.1097/j.pain.0000000000001171
10. Hundehege P, Fernandez-Orth J, Römer P, et al. Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis. Neurosignals. 2018;26(1):77-93. doi:10.1159/000495425
11. Szepanowski F, Winkelhausen M, Steubing RD, Mausberg AK, Kleinschnitz C, Stettner M. LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis. J Neuroinflammation. 2021;18(1):293. Published 2021 Dec 17. doi:10.1186/s12974-021-02350-5
12. Duan Y-W, Chen S-X, Li Q-Y, Zang Y. Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway. International Journal of Molecular Sciences. 2022; 23(13):7191. https://doi.org/10.3390/ijms23137191
13. Royds J, McCrory C. Neuroimmunity and chronic pain. BJA Educ. 2018;18(12):377-383. doi:10.1016/j.bjae.2018.09.003
14. Kavelaars A, Heijnen CJ. Immune regulation of pain: Friend and foe. Sci Transl Med. 2021;13(619):eabj7152. doi:10.1126/scitranslmed.abj7152
15. Kavelaars A, Heijnen CJ. T Cells as Guardians of Pain Resolution. Trends Mol Med. 2021;27(4):302-313. doi:10.1016/j.molmed.2020.12.007
16. Liu, X., Yang, W., Zhu, C. et al. Toll-like receptors and their role in neuropathic pain and migraine. Mol Brain 15, 73 (2022). https://doi.org/10.1186/s13041-022-00960-5
17. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454(7203):445-454. doi:10.1038/nature07204
18. Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14(4):388-405. doi:10.1016/S1474-4422(15)70016-5
19. Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112. Published 2014 Apr 22. doi:10.3389/fncel.2014.00112
20. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942-955. doi:10.1056/NEJMra052130
21. Lim SL, Rodriguez-Ortiz CJ, Kitazawa M. Infection, systemic inflammation, and Alzheimer's disease. Microbes Infect. 2015;17(8):549-556. doi:10.1016/j.micinf.2015.04.004
22. Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16(8):445-457. doi:10.1038/nrn3921
23. Laumet G, Ma J, Robison AJ, Kumari S, Heijnen CJ, Kavelaars A. T Cells as an Emerging Target for Chronic Pain Therapy. Front Mol Neurosci. 2019;12:216. Published 2019 Sep 11. doi:10.3389/fnmol.2019.00216
24. Anolik JH, Looney RJ, Lund FE, Randall TD, Sanz I. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res. 2009;45(2-3):144-158. doi:10.1007/s12026-009-8096-7
25. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3(10):944-950. doi:10.1038/ni833
26. Lee, D.S.W., Rojas, O.L. & Gommerman, J.L. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov 20, 179–199 (2021). https://doi.org/10.1038/s41573-020-00092-2
27. Catrina AI, Svensson CI, Malmström V, Schett G, Klareskog L. Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol. 2017;13(2):79-86. doi:10.1038/nrrheum.2016.200
28. Mauri C, Basma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221-241. doi:10.1146/annurev-immunol-020711-074934
29. Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012;3:302. Published 2012 Oct 10. doi:10.3389/fimmu.2012.00302
30. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572-2581. doi:10.1056/NEJMoa032534
31. Lassen J, Stürner KH, Gierthmühlen J, et al. Protective role of natural killer cells in neuropathic pain conditions. Pain. 2021;162(9):2366-2375. doi:10.1097/j.pain.0000000000002274
32. Lin SJ, Kuo ML, Hsiao HS, et al. Cytotoxic Function and Cytokine Production of Natural Killer Cells and Natural Killer T-Like Cells in Systemic Lupus Erythematosis Regulation with Interleukin-15. Mediators Inflamm. 2019;2019:4236562. Published 2019 Mar 31. doi:10.1155/2019/4236562
33. Hudspeth K, Wang S, Wang J, et al. Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus. Clin Exp Immunol. 2019;196(2):226-236. doi:10.1111/cei.13263
34. Vega-Avelaira D, Géranton SM, Fitzgerald M. Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Mol Pain. 2009;5:70. Published 2009 Dec 10. doi:10.1186/1744-8069-5-70
35. Martínez-Lavín M. Dorsal root ganglia: fibromyalgia pain factory?. Clin Rheumatol. 2021;40(2):783-787. doi:10.1007/s10067-020-05528-z
36. Liu JA, Yu J, Cheung CW. Immune Actions on the Peripheral Nervous System in Pain. Int J Mol Sci. 2021;22(3):1448. Published 2021 Feb 1. doi:10.3390/ijms22031448
37. Watanabe S, Alexander M, Misharin AV, Budinger GRS. The role of macrophages in the resolution of inflammation. J Clin Invest. 2019;129(7):2619-2628. Published 2019 May 20. doi:10.1172/JCI124615
38. Gaudet, A.D., Popovich, P.G. & Ramer, M.S. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8, 110 (2011). https://doi.org/10.1186/1742-2094-8-110
39. Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015;3(10):136. doi:10.3978/j.issn.2305-5839.2015.03.49
40. Li, H., Fu, Q., Philips, K. et al. Leukocyte inflammatory phenotype and function in migraine patients compared with matched non-migraine volunteers: a pilot study. BMC Neurol 22, 278 (2022). https://doi.org/10.1186/s12883-022-02781-4
41. Mangiacavalli S, Corso A, De Amici M, et al. Emergent T-helper 2 profile with high interleukin-6 levels correlates with the appearance of bortezomib-induced neuropathic pain. Br J Haematol. 2010;149(6):916-918. doi:10.1111/j.1365-2141.2010.08138.x
42. Luchting B, Rachinger-Adam B, Zeitler J, et al. Disrupted TH17/Treg balance in patients with chronic low back pain. PLoS One. 2014;9(8):e104883. Published 2014 Aug 14. doi:10.1371/journal.pone.0104883
43. Russo, M.A., Fiore, N.T., van Vreden, C. et al. Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome. J Neuroinflammation 16, 63 (2019). https://doi.org/10.1186/s12974-019-1449-9
44. Heyn, J., Azad, S.C. & Luchting, B. Altered regulation of the T-cell system in patients with CRPS. Inflamm. Res. 68, 1–6 (2019). https://doi.org/10.1007/s00011-018-1182-3
45. Plein LM, Rittner HL. Opioids and the immune system - friend or foe. Br J Pharmacol. 2018;175(14):2717-2725. doi:10.1111/bph.13750
46. Royds J, Cassidy H, Conroy MJ, Dunne MR, Lysaght J, McCrory C. Examination and characterisation of the effect of amitriptyline therapy for chronic neuropathic pain on neuropeptide and proteomic constituents of human cerebrospinal fluid. Brain Behav Immun Health. 2020;10:100184. Published 2020 Dec 7. doi:10.1016/j.bbih.2020.100184
47. Moore D, Galvin D, Conroy MJ, et al. Characterisation of the effects of pulsed radio frequency treatment of the dorsal root ganglion on cerebrospinal fluid cellular and peptide constituents in patients with chronic radicular pain: A randomised, triple-blinded, controlled trial. J Neuroimmunol. 2020;343:577219. doi:10.1016/j.jneuroim.2020.577219
48. Halievski K, Sengar AS, Hicks J, Haight J, Salter MW, Steinberg BE. Cholinergic modulation is independent of T lymphocytes in a mouse model of neuropathic pain. Mol Pain. 2022;18:17448069221076634. doi:10.1177/17448069221076634
49. Hayward A, Levin M, Wolf W, Angelova G, Gilden D. Varicella-zoster virus-specific immunity after herpes zoster. J Infect Dis. 1991;163(4):873-875. doi:10.1093/infdis/163.4.873
50. Maeda D, Akiyama Y, Morikawa T, et al. Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation. PLoS One. 2015;10(11):e0143316. Published 2015 Nov 20. doi:10.1371/journal.pone.0143316
51. Wurth S, Kuenz B, Bsteh G, et al. Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study. PLoS One. 2017;12(8):e0182462. Published 2017 Aug 4. doi:10.1371/journal.pone.0182462
52. Wigerblad G, Bas DB, Fernades-Cerqueira C et al. Autoantibodies to citrullinated proteins may induce joint pain independent of inflammation. Annals of the rheumatic diseases. 2016; 75(4), 730-738.
53. Li M, Peake PW, Charlesworth JA, Tracey DJ, Moalem-Taylor G. Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats. Eur J Neurosci. 2007;26(12):3486-3500. doi:10.1111/j.1460-9568.2007.05971.x
54. Levin ME, Jin JG, Ji RR, et al. Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain. Pain. 2008;137(1):182-201. doi:10.1016/j.pain.2007.11.005
55. Atzeni F, Doria A, Turiel M et al. What is the role of rituximab in the treatment of rheumatoid arthritis? Autoimmun Rev. 2007; 6:553–8. 10.1016/j.autrev.2007.02.004
56. Lassen J, Stürner KH, Gierthmühlen J, et al. Protective role of natural killer cells in neuropathic pain conditions. Pain. 2021;162(9):2366-2375. doi:10.1097/j.pain.0000000000002274
57. Wall PD, Gutnick M. Properties of afferent nerve impulses originating from a neuroma. Nature. 1974;248(5451):740-743. doi:10.1038/248740a0
58. Wall PD, Devor M, Inbal R, et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain. 1979;7(2):103-113. doi:10.1016/0304-3959(79)90002-2
59. Gabay E, Tal M. Pain behavior and nerve electrophysiology in the CCI model of neuropathic pain. Pain. 2004;110(1-2):354-360. doi:10.1016/j.pain.2004.04.021
60. De Vry J, Kuhl E, Franken-Kunkel P, Eckel G. Pharmacological characterization of the chronic constriction injury model of neuropathic pain. Eur J Pharmacol. 2004;491(2-3):137-148. doi:10.1016/j.ejphar.2004.03.051
61. Dowdall T, Robinson I, Meert TF. Comparison of five different rat models of peripheral nerve injury. Pharmacol Biochem Behav. 2005;80(1):93-108. doi:10.1016/j.pbb.2004.10.016
62. Li M, Peake PW, Charlesworth JA, Tracey DJ, Moalem-Taylor G. Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats. Eur J Neurosci. 2007;26(12):3486-3500. doi:10.1111/j.1460-9568.2007.05971.x
63. Levin ME, Jin JG, Ji RR, et al. Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain. Pain. 2008;137(1):182-201. doi:10.1016/j.pain.2007.11.005
64. Dailey AT, Avellino AM, Benthem L et al. Complement depletion reduces macrophage infiltration and activation during Wallerian degeneration and axonal regeneration. Journal of Neuroscience. 1998; 18(17), 6713-6722.
65. de Graaf MT, de Jongste AH, Kraan J, Boonstra JG, Sillevis Smitt PA, Gratama JW. Flow cytometric characterization of cerebrospinal fluid cells. Cytometry B Clin Cytom. 2011;80(5):271-281. doi:10.1002/cyto.b.20603
66. Svenningsson A, Andersen O, Hansson GK, Stemme S. Reduced frequency of memory CD8+ T lymphocytes in cerebrospinal fluid and blood of patients with multiple sclerosis. Autoimmunity. 1995;21(4):231-239. doi:10.3109/08916939509001941
67. Liu XJ, Zhang Y, Liu T, et al. Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res. 2014;24(11):1374-1377. doi:10.1038/cr.2014.106
68. Krukowski K, Eijkelkamp N, Laumet G et al. CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain. J. Neurosci. 2016; 36, 11074–11083. doi: 10.1523/JNEUROSCI.3708-15.2016
69. Laumet G, Dantzer R, Krukowski K et al. N. T lymphocytes are required for resolution of inflammatory pain and depression-like behavior. Brain Behav. Immun. 2016; 57, e5–e6. doi: 10.1016/j.bbi.2016.07.022
70. Laumet G, Edralin JD, Dantzer R, Heijnen CJ, Kavelaars A. Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice. Pain. 2019;160(6):1459-1468. doi:10.1097/j.pain.0000000000001512
71. Zhang XL, Zhang JJ, Chen ZH, et al. Difference of pain vulnerability in adult and juvenile rodents: the role of SIRT1-mediated ClC-3 trafficking in sensory neurons. Pain. 2021;162(6):1882-1896. doi:10.1097/j.pain.0000000000002176
72. Pachman DR, Dockter T, Zekan PJ, et al. A pilot study of minocycline for the prevention of paclitaxel-associated neuropathy: ACCRU study RU221408I. Support Care Cancer. 2017;25(11):3407-3416. doi:10.1007/s00520-017-3760-2
73. Younger DS. Diabetic neuropathy: a clinical and neuropathological study of 107 patients. Neurol Res Int. 2010;2010:140379. doi:10.1155/2010/140379
74. Zhang Y, Chi D. Overexpression of SIRT2 Alleviates Neuropathic Pain and Neuroinflammation Through Deacetylation of Transcription Factor Nuclear Factor-Kappa B. Inflammation. 2018;41(2):569-578. doi:10.1007/s10753-017-0713-3
75. Beier UH, Akimova T, Liu Y, Wang L, Hancock WW. Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells. Curr Opin Immunol. 2011;23(5):670-678. doi:10.1016/j.coi.2011.07.002
76. van Loosdregt J, Brunen D, Fleskens V, Pals CE, Lam EW, Coffer PJ. Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One. 2011;6(4):e19047. Published 2011 Apr 20. doi:10.1371/journal.pone.0019047
77. Heyn J, Luchting B, Hinske LC, Hübner M, Azad SC, Kreth S. miR-124a and miR-155 enhance differentiation of regulatory T cells in patients with neuropathic pain. J Neuroinflammation. 2016;13(1):248. Published 2016 Sep 20. doi:10.1186/s12974-016-0712-6
78. Oza MJ, Kulkarni YA. Formononetin Ameliorates Diabetic Neuropathy by Increasing Expression of SIRT1 and NGF. Chem Biodivers. 2020;17(6):e2000162. doi:10.1002/cbdv.202000162
79. Backonja M, Williams L, Miao X, Katz N, Chen C. Safety and efficacy of neublastin in painful lumbosacral radiculopathy: a randomized, double-blinded, placebo-controlled phase 2 trial using Bayesian adaptive design (the SPRINT trial). Pain. 2017;158(9):1802-1812. doi:10.1097/j.pain.0000000000000983
80. Anand P, Shenoy R, Palmer JE, et al. Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur J Pain. 2011;15(10):1040-1048. doi:10.1016/j.ejpain.2011.04.005
81. Goebel A, Bisla J, Carganillo R, et al. A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial). Southampton (UK): NIHR Journals Library; November 2017.
82. Chen G, Kim YH, Li H, et al. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1 [published correction appears in Nat Neurosci. 2019 Mar;22(3):503]. Nat Neurosci. 2017;20(7):917-926. doi:10.1038/nn.4571
83. Li M, Peake PW, Charlesworth JA, Tracey DJ, Moalem-Taylor G. Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats. Eur J Neurosci. 2007;26(12):3486-3500. doi:10.1111/j.1460-9568.2007.05971.x
84. Labuz D, Schmidt Y, Schreiter A, Rittner HL, Mousa SA, Machelska H. Immune cell-derived opioids protect against neuropathic pain in mice [published correction appears in J Clin Invest. 2009 Apr;119(4):1051]. J Clin Invest. 2009;119(2):278-286. doi:10.1172/JCI36246
85. Börner C, Lanciotti S, Koch T, Höllt V, Kraus J. μ opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013;263(1-2):35-42. doi:10.1016/j.jneuroim.2013.07.012
86. Cornwell WD, Lewis MG, Fan X, Rappaport J, Rogers TJ. Effect of chronic morphine administration on circulating T cell population dynamics in rhesus macaques. J Neuroimmunol. 2013;265(1-2):43-50. doi:10.1016/j.jneuroim.2013.09.013
87. Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience. 2004;129(3):767-777. doi:10.1016/j.neuroscience.2004.08.035
88. 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):1916-1931. doi:10.1016/j.pain.2012.06.005
89. Baddack-Werncke U, Busch-Dienstfertig M, González-Rodríguez S, et al. Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis. J Neuroinflammation. 2017;14(1):30. Published 2017 Feb 6. doi:10.1186/s12974-017-0804-y
90. Duffy SS, Keating BA, Moalem-Taylor G. Adoptive Transfer of Regulatory T Cells as a Promising Immunotherapy for the Treatment of Multiple Sclerosis. Front Neurosci. 2019;13:1107. Published 2019 Oct 15. doi:10.3389/fnins.2019.01107
91. Laumet G, Edralin JD, Chiang AC, Dantzer R, Heijnen CJ, Kavelaars A. Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling. Neuropsychopharmacology. 2018;43(13):2597-2605. doi:10.1038/s41386-018-0154-1