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Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems

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Abstract

Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.

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References

  1. Reale M, Conti L, Velluto D (2018) Immune and inflammatory-mediated disorders: from bench to bedside. J Immunol Res 2018

  2. Bellinger DL, Lorton D (2018) Sympathetic nerve hyperactivity in the spleen: causal for nonpathogenic-driven chronic immune-mediated inflammatory diseases (IMIDs)? Int J Mol Sci 19(4):1188

    Article  Google Scholar 

  3. García M et al (2020) Impact of immune-mediated diseases in inflammatory bowel disease and implications in therapeutic approach. Sci Rep 10(1):1–9

    Article  Google Scholar 

  4. Procaccini C et al (2014) Neuro-endocrine networks controlling immune system in health and disease. Front Immunol 5:143

    Article  Google Scholar 

  5. Dhaiban S et al (2021) Role of peripheral immune cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Sci 3(1):12

    Article  Google Scholar 

  6. Capellino S (2020) Dopaminergic agents in rheumatoid arthritis. J Neuroimmune Pharmacol 15(1):48–56

    Article  Google Scholar 

  7. Halling ML et al (2017) Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases. World J Gastroenterol 23(33):6137

    Article  Google Scholar 

  8. Khalil M, Zhang Z, Engel MA (2019) Neuro-immune networks in gastrointestinal disorders. Visc Med 1(1):52–60

    Article  Google Scholar 

  9. Ananthakrishnan AN et al (2018) Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol 15(1):39–49

    Article  Google Scholar 

  10. Burgaletto C et al (2020) The immune system on the TRAIL of Alzheimer’s disease. J Neuroinflammation 17(1):1–11

    Article  Google Scholar 

  11. Pajares M et al (2020) Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells 9(7):1687

    Article  Google Scholar 

  12. Klein JR (2021) Dynamic interactions between the immune system and the neuroendocrine system in health and disease. Front Endocrinol 12:278

    Article  Google Scholar 

  13. Webster JI, Tonelli L, Sternberg EM (2002) Neuroendocrine regulation of immunity. Annu Rev Immunol 20(1):125–163

    Article  Google Scholar 

  14. Tsoli M, Boutzios G, Kaltsas G (2019) Immune system effects on the endocrine system, in Endotext [Internet]. MDText.com, Inc.

  15. Terrando N, Pavlov VA (2018) Neuro-immune interactions in inflammation and autoimmunity. Front Immunol 9:772

    Article  Google Scholar 

  16. Pongratz G, Straub RH (2014) The sympathetic nervous response in inflammation. Arthritis Res Ther 16(6):504

    Article  Google Scholar 

  17. Kerage D et al (2019) Interaction of neurotransmitters and neurochemicals with lymphocytes. J Neuroimmunol 332:99–111

    Article  Google Scholar 

  18. Pacheco R, Riquelme E, Kalergis AM (2010) Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands. Cent Nerv Syst Agents Med Chem (Formerly Current Medicinal Chemistry-Central Nervous System Agents) 10(1):65–83

    Article  Google Scholar 

  19. Dantzer R (2018) Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev 98(1):477–504

    Article  Google Scholar 

  20. Hodo TW et al (2020) Critical neurotransmitters in the neuroimmune network. Front Immunol 11:1869

    Article  Google Scholar 

  21. Pavlov VA, Tracey KJ (2015) Neural circuitry and immunity. Immunol Res 63(1–3):38–57

    Article  Google Scholar 

  22. Huston JM (2012) The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis. Surg Infect 13(4):187–193

    Article  Google Scholar 

  23. Taub DD (2008) Neuroendocrine interactions in the immune system. Cell Immunol 252(1–2):1

    Article  Google Scholar 

  24. Deckx N, Lee WP, Berneman ZN, Cools N (2013) Neuroendocrine immunoregulation in multiple sclerosis. Clin Dev Immunol 2013:705232. https://doi.org/10.1155/2013/705232. Epub 2013 Dec 8

  25. Chen L et al (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9(6):7204

    Article  Google Scholar 

  26. Müller N (2018) Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. Schizophr Bull 44(5):973–982

    Article  Google Scholar 

  27. Sam C, Bordoni B (2022) Physiology, Acetylcholine. In: StatPearls [Internet]. StatPearls Publishing

  28. Tiwari P et al (2013) Basic and modern concepts on cholinergic receptor: a review. Asian Pacific J Trop Dis 3(5):413–420

    Article  Google Scholar 

  29. Hoover DB (2017) Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol Ther 179:1–16

    Article  Google Scholar 

  30. Fujii T et al (2017) Expression and function of the cholinergic system in immune cells. Front Immunol 8:1085

    Article  Google Scholar 

  31. Bosmans G et al (2017) Cholinergic modulation of type 2 immune responses. Front Immunol 8:1873

    Article  Google Scholar 

  32. Báez-Pagán CA, Delgado-Vélez M, Lasalde-Dominicci JA (2015) Activation of the macrophage α7 nicotinic acetylcholine receptor and control of inflammation. J Neuroimmune Pharmacol 10(3):468–476

    Article  Google Scholar 

  33. Zoli M et al (2018) Neuronal and extraneuronal nicotinic acetylcholine receptors. Curr Neuropharmacol 16(4):338–349

    Article  Google Scholar 

  34. McAllen RM et al (2015) The interface between cholinergic pathways and the immune system and its relevance to arthritis. Arthritis Res Ther 17(1):1–9

    Article  Google Scholar 

  35. Kaushik V et al (2018) Acetylcholinesterase inhibitors: beneficial effects on comorbidities in patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen® 33(2):73–85

    Article  Google Scholar 

  36. Di Bari M et al (2016) Dysregulated homeostasis of acetylcholine levels in immune cells of RR-multiple sclerosis patients. Int J Mol Sci 17(12):2009

    Article  Google Scholar 

  37. Zabrodskii P (2011) Effect of acetylcholine on mortality of mice from sepsis and proinflammatory cytokine production. Bull Exp Biol Med 150(3):340

    Article  Google Scholar 

  38. Mizrachi T et al (2021) Suppression of neuroinflammation by an allosteric agonist and positive allosteric modulator of the α7 nicotinic acetylcholine receptor GAT107. J Neuroinflammation 18(1):1–14

    Article  Google Scholar 

  39. Nicoletti CG et al (2019) Treatment with dimethyl fumarate enhances cholinergic transmission in multiple sclerosis. CNS Drugs 33(11):1133–1139

    Article  Google Scholar 

  40. Kooi E-J et al (2011) Cholinergic imbalance in the multiple sclerosis hippocampus. Acta Neuropathol 122(3):313–322

    Article  Google Scholar 

  41. Di Bari M, Pinto GD, Reale M, Mengod G, Tata AM (2017) Cholinergic system and neuroinflammation: implication in multiple sclerosis. Cent Nerv Syst Agents Med Chem 17(2):109–115. https://doi.org/10.2174/1871524916666160822115133

    Article  Google Scholar 

  42. Miceli P, Jacobson K (2003) Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats. Auton Neurosci 105(1):16–24

    Article  Google Scholar 

  43. Hayashi S et al (2014) Nicotine suppresses acute colitis and colonic tumorigenesis associated with chronic colitis in mice. Am J Physiol-Gastrointest Liver Physiol 307(10):G968–G978

    Article  Google Scholar 

  44. Ghia JE et al (2006) The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131(4):1122–1130

    Article  Google Scholar 

  45. Munyaka P et al (2014) Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+ CD25-T cells in experimental colitis. PLoS One 9(10):e109272

    Article  Google Scholar 

  46. Ji H et al (2014) Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol 7(2):335–347

    Article  Google Scholar 

  47. Pai YC, Yu LCH (2020) Is “Cholinergic” stimulus useful for ulcerative colitis treatment? Dig Dis Sci 65(1):6–8. https://doi.org/10.1007/s10620-019-05933-8

    Article  Google Scholar 

  48. Bai A, Guo Y, Lu N (2007) The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 66(5):538–545

    Article  Google Scholar 

  49. Al-Khotani A, Alstergren P (2017) Acetylcholine suppresses release of interleukin-6 in fibroblast-like synov-iocytes in rheumatoid arthritis. J Dent Oro Surg 2(1):126

    Google Scholar 

  50. Yabut JM et al (2019) Emerging roles for serotonin in regulating metabolism: new implications for an ancient molecule. Endocr Rev 40(4):1092–1107

    Article  Google Scholar 

  51. Fitzpatrick PF (2003) Mechanism of aromatic amino acid hydroxylation. Biochemistry 42(48):14083–14091

    Article  Google Scholar 

  52. Berger M, Gray JA, Roth BL (2009) The expanded biology of serotonin. Annu Rev Med 60:355–366

    Article  Google Scholar 

  53. Gershon MD (2013) 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 20(1):14

    Article  Google Scholar 

  54. Ahern GP (2011) 5-HT and the immune system. Curr Opin Pharmacol 11(1):29–33

    Article  Google Scholar 

  55. Herr N, Bode C, Duerschmied D (2017) The effects of serotonin in immune cells. Front Cardiovasc Med 4:48

    Article  Google Scholar 

  56. Arreola R, Becerril-Villanueva E, Cruz-Fuentes C, Velasco-Velázquez MA, Garcés-Alvarez ME, Hurtado-Alvarado G, Quintero-Fabian S, Pavón L (2015) Immunomodulatory effects mediated by serotonin. J Immunol Res 2015:354957. https://doi.org/10.1155/2015/354957. Epub 2015 Apr 19

  57. Nowak EC et al (2012) Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med 209(11):2127–2135

    Article  Google Scholar 

  58. Chabbi-Achengli Y et al (2016) Serotonin is involved in autoimmune arthritis through Th17 immunity and bone resorption. Am J Pathol 186(4):927–937

    Article  Google Scholar 

  59. Bernardes M et al (2017) Serum serotonin levels and bone in rheumatoid arthritis patients. Rheumatol Int 37(11):1891–1898

    Article  Google Scholar 

  60. Coates M et al (2017) The many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease. Aliment Pharmacol Ther 46(6):569–580

    Article  Google Scholar 

  61. Shajib MS et al (2019) Characterization of serotonin signaling components in patients with inflammatory bowel disease. J Can Assoc Gastroenterol 2(3):132–140

    Article  Google Scholar 

  62. Li N et al (2011) Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol 178(2):662–671

    Article  Google Scholar 

  63. Motavallian A et al (2013) Involvement of 5HT3 receptors in anti-inflammatory effects of tropisetron on experimental TNBS-induced colitis in rat. BioImpacts: BI 3(4):169

    Google Scholar 

  64. Sittipo P et al (2022) The function of gut microbiota in immune-related neurological disorders: a review. J Neuroinflammation 19(1):1–17

    Article  Google Scholar 

  65. Kwon YH et al (2019) Modulation of gut microbiota composition by serotonin signaling influences intestinal immune response and susceptibility to colitis. Cell Mol Gastroenterol Hepatol 7(4):709–728

    Article  Google Scholar 

  66. Sochocka M et al (2019) The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease—a critical review. Mol Neurobiol 56(3):1841–1851

    Article  Google Scholar 

  67. Pérez LP, González RS, Lázaro EB (2015) Treatment of mood disorders in multiple sclerosis. Curr Treat Options Neurol 17(1):1–11

    Article  Google Scholar 

  68. Stamoula E et al (2021) Antidepressants on multiple sclerosis: a review of in vitro and in vivo models. Front Immunol 12:677879

    Article  Google Scholar 

  69. San Hernandez AM, Singh C, Valero DJ, Nisar J, Ramirez JIT, Kothari KK, Isola S, Gordon DK (2020) Multiple sclerosis and serotonin: potential therapeutic applications. Cureus 12(11):e11293

    Google Scholar 

  70. Aboukhatwa M, Dosanjh L, Luo Y (2010) Antidepressants are a rational complementary therapy for the treatment of Alzheimer’s disease. Mol Neurodegener 5(1):1–17

    Article  Google Scholar 

  71. Hall BJ, Hamlin PJ, Gracie DJ, Ford AC (2018) The effect of antidepressants on the course of inflammatory bowel disease. Can J Gastroenterol Hepatol 2018:2047242. https://doi.org/10.1155/2018/2047242

    Article  Google Scholar 

  72. Matt S, Gaskill P (2019) Where is dopamine and how do immune cells see it?: dopamine-mediated immune cell function in health and disease. J Neuroimmune Pharmacol 15(1):114–164. https://doi.org/10.1007/s11481-019-09851-4

    Article  Google Scholar 

  73. Levite M (2012) Dopamine in the immune system: dopamine receptors in immune cells, potent effects, endogenous production and involvement in immune and neuropsychiatric diseases. In: Nerve-Driven Immunity. Springer, pp 1–45

  74. Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, Quintero-Fabián S, Pavón L (2016) Immunomodulatory effects mediated by dopamine. J Immunol Res 2016:3160486. https://doi.org/10.1155/2016/3160486. Epub 2016 Oct 4

  75. Gurevich EV, Gainetdinov RR, Gurevich VV (2016) G protein-coupled receptor kinases as regulators of dopamine receptor functions. Pharmacol Res 111:1–16

    Article  Google Scholar 

  76. Wang X et al (2019) The prospective value of dopamine receptors on bio-behavior of tumor. J Cancer 10(7):1622

    Article  Google Scholar 

  77. Mackie P et al (2018) The dopamine transporter: an unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease. Brain Behav Immun 70:21–35

    Article  Google Scholar 

  78. Vidal PM, Pacheco R (2019) Targeting the dopaminergic system in autoimmunity. J Neuroimmune Pharmacol 15(1):57–73. https://doi.org/10.1007/s11481-019-09834-5

    Article  Google Scholar 

  79. Hoeger S et al (2008) Donor dopamine treatment in brain dead rats is associated with an improvement in renal function early after transplantation and a reduction in renal inflammation. Transpl Int 21(11):1072–1080

    Google Scholar 

  80. Beck GC et al (2001) Modulation of chemokine production in lung microvascular endothelial cells by dopamine is mediated via an oxidative mechanism. Am J Respir Cell Mol Biol 25(5):636–643

    Article  Google Scholar 

  81. Kapper S et al (2002) Modulation of chemokine production and expression of adhesion molecules in renal tubular epithelial and endothelial cells by catecholamines. Transplantation 74(2):253–260

    Article  Google Scholar 

  82. Capellino S et al (2014) Increased expression of dopamine receptors in synovial fibroblasts from patients with rheumatoid arthritis: inhibitory effects of dopamine on interleukin-8 and interleukin-6. Arthritis Rheumatol 66(10):2685–2693

    Article  Google Scholar 

  83. Capellino S (2019) Dopaminergic agents in rheumatoid arthritis. J Neuroimmune Pharmacol 15(1):48–56

    Article  Google Scholar 

  84. Nakano K et al (2011) Dopamine induces IL-6–dependent IL-17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol 186(6):3745–3752

    Article  Google Scholar 

  85. van Nie L et al (2020) Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis. Sci Rep 10(1):1–13

    Google Scholar 

  86. Wieber K et al (2022) Dopamine receptor 1 expressing B cells exert a proinflammatory role in female patients with rheumatoid arthritis. Sci Rep 12(1):1–15

    Article  Google Scholar 

  87. Magro F et al (2002) Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci 47(1):216–224

    Article  Google Scholar 

  88. Magro F et al (2004) Decreased availability of intestinal dopamine in transmural colitis may relate to inhibitory effects of interferon-γ upon L-DOPA uptake. Acta Physiol Scand 180(4):379–386

    Article  Google Scholar 

  89. Magro F et al (2006) Dopamine D 2 receptor polymorphisms in inflammatory bowel disease and the refractory response to treatment. Dig Dis Sci 51(11):2039–2044

    Article  Google Scholar 

  90. Cosentino M et al (2007) Human CD4+ CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood 109(2):632–642

    Article  Google Scholar 

  91. Pacheco R, Contreras F, Zouali M (2014) The dopaminergic system in autoimmune diseases. Front Immunol 5:117

    Article  Google Scholar 

  92. Cosentino M, Zaffaroni M, Marino F (2014) Levels of mRNA for dopaminergic receptor D5 in circulating lymphocytes may be associated with subsequent response to interferon-β in patients with multiple sclerosis. J Neuroimmunol 277(1–2):193–196

    Article  Google Scholar 

  93. Levite M, Marino F, Cosentino M (2017) Dopamine, T cells and multiple sclerosis (MS). J Neural Transm 124(5):525–542

    Article  Google Scholar 

  94. Giorelli M, Livrea P, Trojano M (2005) Dopamine fails to regulate activation of peripheral blood lymphocytes from multiple sclerosis patients: effects of IFN-β. J Interferon Cytokine Res 25(7):395–406

    Article  Google Scholar 

  95. Lieberknecht V et al (2017) Pramipexole, a dopamine D2/D3 receptor-preferring agonist, prevents experimental autoimmune encephalomyelitis development in mice. Mol Neurobiol 54(2):1033–1045

    Article  Google Scholar 

  96. Zhu Y et al (2020) 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine Induced Parkinson’s disease in mouse: potential association between neurotransmitter disturbance and gut microbiota dysbiosis. ACS Chem Neurosci 11(20):3366–3376

    Article  Google Scholar 

  97. Fung TC (2020) The microbiota-immune axis as a central mediator of gut-brain communication. Neurobiol Dis 136:104714

    Article  Google Scholar 

  98. Zhang T et al (2022) Gut microbiota relieves inflammation in the substantia nigra of chronic Parkinson’s disease by protecting the function of dopamine neurons. Exp Ther Med 23(1):1–10

    Article  Google Scholar 

  99. Hamamah S et al (2022) Role of microbiota-gut-brain axis in regulating dopaminergic signaling. Biomedicines 10(2):436

    Article  Google Scholar 

  100. Everington EA et al (2018) Molecular characterization of GABA-A receptor subunit diversity within major peripheral organs and their plasticity in response to early life psychosocial stress. Front Mol Neurosci 11:18

    Article  Google Scholar 

  101. Sigel E, Steinmann ME (2012) Structure, function, and modulation of GABAA receptors. J Biol Chem 287(48):40224–40231

    Article  Google Scholar 

  102. Jin Z, Mendu SK, Birnir B (2013) GABA is an effective immunomodulatory molecule. Amino Acids 45(1):87–94

    Article  Google Scholar 

  103. Wu C et al (2017) The immunological function of GABAergic system. Front Biosci (Landmark edition) 22:1162

    Article  Google Scholar 

  104. Auteri M, Zizzo MG, Serio R (2015) GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol Res 93:11–21

    Article  Google Scholar 

  105. Han D et al (2007) Wound healing activity of gamma-aminobutyric Acid (GABA) in rats. J Microbiol Biotechnol 17(10):1661–1669

    Google Scholar 

  106. Reyes-García MG et al (2007) GABA (A) receptor subunits RNA expression in mice peritoneal macrophages modulate their IL-6/IL-12 production. J Neuroimmunol 188(1–2):64–68

    Article  Google Scholar 

  107. Tian J et al (1999) GABAA receptors mediate inhibition of T cell responses. J Neuroimmunol 96(1):21–28

    Article  Google Scholar 

  108. Song D-K et al (1998) Central GABAA and GABAB receptor modulation of basal and stress-induced plasma interleukin-6 levels in mice. J Pharmacol Exp Ther 287(1):144–149

    Google Scholar 

  109. Sanders RD et al (2013) Benzodiazepine augmented γ-amino-butyric acid signaling increases mortality from pneumonia in mice. Crit Care Med 41(7):1627

    Article  Google Scholar 

  110. Alam S et al (2006) Human peripheral blood mononuclear cells express GABAA receptor subunits. Mol Immunol 43(9):1432–1442

    Article  Google Scholar 

  111. Tian J et al (2004) γ-Aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J Immunol 173(8):5298–5304

    Article  Google Scholar 

  112. Demakova E, Korobov V, Lemkina L (2003) Determination of gamma-aminobutyric acid concentration and activity of glutamate decarboxylase in blood serum of patients with multiple sclerosis. Klin Lab Diagn 4:15

    Google Scholar 

  113. Bhat R et al (2010) Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci 107(6):2580–2585

    Article  Google Scholar 

  114. Ma X et al (2018) Activation of GABAA receptors in colon epithelium exacerbates acute colitis. Front Immunol 9:987

    Article  Google Scholar 

  115. Tian J et al (2011) Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity 44(6):465–470

    Article  Google Scholar 

  116. Kelley JM, Hughes LB, Bridges SL (2008) Does gamma-aminobutyric acid (GABA) influence the development of chronic inflammation in rheumatoid arthritis? J Neuroinflammation 5(1):1–5

    Article  Google Scholar 

  117. Wiatrak B et al (2022) The role of the microbiota-gut-brain axis in the development of Alzheimer’s disease. Int J Mol Sci 23(9):4862

    Article  Google Scholar 

  118. Platt SR (2007) The role of glutamate in central nervous system health and disease–a review. Vet J 173(2):278–286

    Article  Google Scholar 

  119. Haroon E, Miller AH, Sanacora G (2017) Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology 42(1):193–215

    Article  Google Scholar 

  120. McCullumsmith RE, Sanacora G (2015) Regulation of extrasynaptic glutamate levels as a pathophysiological mechanism in disorders of motivation and addiction. Neuropsychopharmacology 40(1):254

    Article  Google Scholar 

  121. Wang J et al (2020) Molecular mechanisms of glutamate toxicity in Parkinson’s disease. Front Neurosci 14:1201

    Article  Google Scholar 

  122. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    Article  Google Scholar 

  123. Malarkey EB, Parpura V (2008) Mechanisms of glutamate release from astrocytes. Neurochem Int 52(1–2):142–154

    Article  Google Scholar 

  124. Duman RS (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci 16(1):11

    Article  Google Scholar 

  125. McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41(1):3–23

    Article  Google Scholar 

  126. Allam SL et al (2015) Synaptic efficacy as a function of ionotropic receptor distribution: a computational study. PLoS One 10(10):e0140333

    Article  Google Scholar 

  127. Allam SL et al (2012) A computational model to investigate astrocytic glutamate uptake influence on synaptic transmission and neuronal spiking. Front Comput Neurosci 6:70

    Article  Google Scholar 

  128. Hansen AM, Caspi RR (2010) Glutamate joins the ranks of immunomodulators. Nat Med 16(8):856–858

    Article  Google Scholar 

  129. East SP, Gerlach K (2010) mGluR4 positive allosteric modulators with potential for the treatment of Parkinson’s disease: WO09010455. Expert Opin Ther Pat 20(3):441–445

    Article  Google Scholar 

  130. Johnson KA, Conn PJ, Niswender CM (2009) Glutamate receptors as therapeutic targets for Parkinson’s disease. CNS Neurol Disord-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 8(6):475–491

    Google Scholar 

  131. Frigo M et al (2012) Glutamate and multiple sclerosis. Curr Med Chem 19(9):1295–1299

    Article  Google Scholar 

  132. Chang C-H, Lin C-H, Lane H-Y (2020) d-glutamate and gut microbiota in Alzheimer’s disease. Int J Mol Sci 21(8):2676

    Article  Google Scholar 

  133. O’Neill E, Harkin A (2018) Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects: implications for Parkinson’s disease. Neural Regen Res 13(8):1332

    Article  Google Scholar 

  134. Jiang L et al (2015) A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis. Glia 63(6):1057–1072

    Article  Google Scholar 

  135. Russo CD et al (2004) Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1β production. J Neuroinflammation 1(1):1–15

    Article  Google Scholar 

  136. Culmsee C, Semkova I, Krieglstein J (1999) NGF mediates the neuroprotective effect of the β2-adrenoceptor agonist clenbuterol in vitro and in vivo: evidence from an NGF-antisense study. Neurochem Int 35(1):47–57

    Article  Google Scholar 

  137. Simonini MV et al (2010) Increasing CNS noradrenaline reduces EAE severity. J Neuroimmune Pharmacol 5(2):252–259

    Article  Google Scholar 

  138. Vollmar P et al (2009) The antidepressant venlafaxine ameliorates murine experimental autoimmune encephalomyelitis by suppression of pro-inflammatory cytokines. Int J Neuropsychopharmacol 12(4):525–536

    Article  Google Scholar 

  139. Benarroch EE (2009) The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology 73(20):1699–1704

    Article  Google Scholar 

  140. Samuels E, Szabadi E (2008) Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans. Curr Neuropharmacol 6(3):254–285

    Article  Google Scholar 

  141. Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10(3):211–223

    Article  Google Scholar 

  142. Marien MR, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Rev 45(1):38–78

    Article  Google Scholar 

  143. Polak PE, Kalinin S, Feinstein DL (2011) Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 134(3):665–677

    Article  Google Scholar 

  144. Chalermpalanupap T et al (2013) Targeting norepinephrine in mild cognitive impairment and Alzheimer’s disease. Alzheimers Res Ther 5(2):1–9

    Article  Google Scholar 

  145. Heneka M et al (2002) Noradrenergic depletion of the cortex potentiates amyloid beta-induced inflammation: implications for Alzheimer’s disease. Neurobiol Aging. Elsevier Science Inc 360 Park Ave South, New York 10010–1710

  146. Heneka MT et al (2003) Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression. J Neurochem 85(2):387–398

    Article  Google Scholar 

  147. Butkovich LM, Houser MC, Tansey MG (2018) α-synuclein and noradrenergic modulation of immune cells in Parkinson’s disease pathogenesis. Front Neurosci 12:626

    Article  Google Scholar 

  148. Johnson M, Young AD, Marriott I (2017) The therapeutic potential of targeting substance P/NK-1R interactions in inflammatory CNS disorders. Front Cell Neurosci 10:296

    Article  Google Scholar 

  149. Krause JE, Takeda Y, Hershey AD (1992) Structure, functions, and mechanisms of substance P receptor action. J Investig Dermatol 98(6):S2-7

    Article  Google Scholar 

  150. Severini C et al (2002) The tachykinin peptide family. Pharmacol Rev 54(2):285–322

    Article  Google Scholar 

  151. Zhang Z et al (2017) Up-regulated expression of substance P in CD8+ T cells and NK1R on monocytes of atopic dermatitis. J Transl Med 15(1):93

    Article  Google Scholar 

  152. Hafidi A et al (2002) Comparative distribution of NK1, NK2, and NK3 receptors in the rat brainstem auditory nuclei. Brain Res 947(2):299–306

    Article  Google Scholar 

  153. Harrison TA, Hoover DB, King MS (2004) Distinct regional distributions of NK1 and NK3 neurokinin receptor immunoreactivity in rat brainstem gustatory centers. Brain Res Bull 63(1):7–17

    Article  Google Scholar 

  154. Todd AJ, McGill MM, Shehab SA (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur J Neurosci 12(2):689–700

    Article  Google Scholar 

  155. Feistritzer C et al (2003) Natural killer cell functions mediated by the neuropeptide substance P. Regul Pept 116(1–3):119–126

    Article  Google Scholar 

  156. Payan DG, Brewster D, Goetzl EJ (1983) Specific stimulation of human T lymphocytes by substance P. J Immunol 131(4):1613–1615

    Article  Google Scholar 

  157. van der Kleij HP et al (2003) Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol 171(4):2074–2079

    Article  Google Scholar 

  158. Germonpre P et al (1999) Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells. Eur Respir J 14(4):776–782

    Article  Google Scholar 

  159. Chauhan VS et al (2008) Neurogenic exacerbation of microglial and astrocyte responses to Neisseria meningitidis and Borrelia burgdorferi. J Immunol 180(12):8241–8249

    Article  Google Scholar 

  160. Marriott I, Bost KL (2001) Expression of authentic substance P receptors in murine and human dendritic cells. J Neuroimmunol 114(1–2):131–141

    Article  Google Scholar 

  161. Levite M (2008) Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors. Curr Opin Pharmacol 8(4):460–471

    Article  Google Scholar 

  162. Martinez AN, Philipp MT (2016) Substance P and antagonists of the neurokinin-1 receptor in neuroinflammation associated with infectious and neurodegenerative diseases of the central nervous system. J Neurol Neuromed 1(2):29

    Article  Google Scholar 

  163. Nessler S et al (2006) Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist—a putative role for substance P in CNS inflammation. J Neuroimmunol 179(1–2):1–8

    Article  Google Scholar 

  164. Kang HS et al (2004) Neurokinin receptors: relevance to the emerging immune system. Arch Immunol Ther Exp-Engl Ed 52(5):338–347

    Google Scholar 

  165. Mashaghi A et al (2016) Neuropeptide substance P and the immune response. Cell Mol Life Sci 73(22):4249–4264

    Article  Google Scholar 

  166. Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro-and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7(1):22–30

    Article  Google Scholar 

  167. Ho W-Z et al (1997) Human monocytes and macrophages express substance P and neurokinin-1 receptor. J Immunol 159(11):5654–5660

    Article  Google Scholar 

  168. Monastyrskaya K et al (2005) The NK1 receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity. J Biol Chem 280(8):7135–7146

    Article  Google Scholar 

  169. Hickey WF (1999) Leukocyte traffic in the central nervous system: the participants and their roles. In: Seminars in immunology, vol 11, no 2. Academic Press, pp 125–137

  170. Whitney NP et al (2009) Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J Neurochem 108(6):1343–1359

    Article  Google Scholar 

  171. Lu H-C, Mackie K (2016) An introduction to the endogenous cannabinoid system. Biol Psychiat 79(7):516–525

    Article  Google Scholar 

  172. Cabral GA, Ferreira GA, Jamerson MJ (2015) Endocannabinoids and the immune system in health and disease. In: Endocannabinoids. Springer, pp 185–211

  173. Haugh O et al (2016) The emerging role of the cannabinoid receptor family in peripheral and neuro-immune interactions. Curr Drug Targets 17(16):1834–1840

    Article  Google Scholar 

  174. Thompson Z et al (2017) Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. Physiol Behav 170:141–150

    Article  Google Scholar 

  175. Patti F et al (2016) Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J Neurol Neurosurg Psychiatry 87(9):944–951

    Article  Google Scholar 

  176. Sido JM, Nagarkatti PS, Nagarkatti M (2016) Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed-type hypersensitivity. Eur J Immunol 46(6):1472–1479

    Article  Google Scholar 

  177. Chen D-J et al (2017) Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin 38(3):312–316

    Article  Google Scholar 

  178. Malfitano AM, Basu S, Maresz K, Bifulco M, Dittel BN (2014) What we know and do not know about the cannabinoid receptor 2 (CB2). Semin Immunol 26(5):369–79. https://doi.org/10.1016/j.smim.2014.04.002

    Article  Google Scholar 

  179. Dittel B (2008) Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor. Br J Pharmacol 153(2):271–276

    Article  Google Scholar 

  180. Cencioni MT et al (2010) Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB 2 receptors. PLoS One 5(1):e8688

    Article  Google Scholar 

  181. Gentili M et al (2019) Selective CB2 inverse agonist JTE907 drives T cell differentiation towards a Treg cell phenotype and ameliorates inflammation in a mouse model of inflammatory bowel disease. Pharmacol Res 141:21–31

    Article  Google Scholar 

  182. Pacifici R et al (2003) Modulation of the immune system in cannabis users. JAMA 289(15):1929–1931

    Article  Google Scholar 

  183. Fraguas-Sánchez AI, Torres-Suárez AI (2018) Medical use of cannabinoids. Drugs 78(16):1665–1703

    Article  Google Scholar 

  184. Oláh A, Szekanecz Z, Bíró T (2017) Targeting cannabinoid signaling in the immune system:“High”-ly exciting questions, possibilities, and challenges. Front Immunol 8:1487

    Article  Google Scholar 

  185. Katchan V, David P, Shoenfeld Y (2016) Cannabinoids and autoimmune diseases: a systematic review. Autoimmun Rev 15(6):513–528

    Article  Google Scholar 

  186. Katz-Talmor D et al (2018) Cannabinoids for the treatment of rheumatic diseases—where do we stand? Nat Rev Rheumatol 14(8):488–498

    Article  Google Scholar 

  187. Lehmann C et al (2016) Experimental cannabidiol treatment reduces early pancreatic inflammation in type 1 diabetes. Clin Hemorheol Microcirc 64(4):655–662

    Article  Google Scholar 

  188. Hryhorowicz S, Kaczmarek-Ryś M, Zielińska A, Scott RJ, Słomski R, Pławski A (2021) Endocannabinoid system as a promising therapeutic target in inflammatory bowel disease–a systematic review. Front Immunol 12:790803. https://doi.org/10.3389/fimmu.2021.790803

    Article  Google Scholar 

  189. Gado F et al (2018) Traditional uses of cannabinoids and new perspectives in the treatment of multiple sclerosis. Medicines 5(3):91

    Article  Google Scholar 

  190. Zajicek JP et al (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 76(12):1664–1669

    Article  Google Scholar 

  191. Reynoso-Moreno I et al (2021) Selective endocannabinoid reuptake inhibitor WOBE437 reduces disease progression in a mouse model of multiple sclerosis. ACS Pharmacol Transl Sci 4(2):765–779

    Article  Google Scholar 

  192. Corder G, Castro DC, Bruchas MR, Scherrer G (2018) Endogenous and exogenous opioids in pain. Annu Rev Neurosci 41:453–473. https://doi.org/10.1146/annurev-neuro-080317-061522

    Article  Google Scholar 

  193. Henry MS, Gendron L, Tremblay ME, Drolet G (2017) Enkephalins: endogenous analgesics with an emerging role in stress resilience. Neural Plast 2017:1546125. https://doi.org/10.1155/2017/1546125

    Article  Google Scholar 

  194. Pasternak GW (2018) Mu opioid pharmacology: 40 years to the promised land. Adv Pharmacol 82:261–291. https://doi.org/10.1016/bs.apha.2017.09.006

    Article  Google Scholar 

  195. Valentino RJ, Volkow ND (2018) Untangling the complexity of opioid receptor function. Neuropsychopharmacology 43(13):2514–2520

    Article  Google Scholar 

  196. Ironside M et al (2018) Brain mechanisms mediating effects of stress on reward sensitivity. Curr Opin Behav Sci 22:106–113

    Article  Google Scholar 

  197. Manninen S et al (2017) Social laughter triggers endogenous opioid release in humans. J Neurosci 37(25):6125–6131

    Article  Google Scholar 

  198. Hua S (2016) Neuroimmune interaction in the regulation of peripheral opioid-mediated analgesia in inflammation. Front Immunol 7:293

    Article  Google Scholar 

  199. Brack A, Rittner HL, Stein C (2011) Immunosuppressive effects of opioids—clinical relevance. J Neuroimmune Pharmacol 6(4):490–502

    Article  Google Scholar 

  200. Cechova K et al (2018) Up-regulation of μ-, δ-and κ-opioid receptors in concanavalin A-stimulated rat spleen lymphocytes. J Neuroimmunol 321:12–23

    Article  Google Scholar 

  201. Roy S et al (2011) Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J Neuroimmune Pharmacol 6(4):442

    Article  Google Scholar 

  202. Mørch H, Pedersen BK (1995) β-Endorphin and the immune system-possible role in autoimmune diseases. Autoimmunity 21(3):161–171

    Article  Google Scholar 

  203. Zhang C et al (2015) Beta-endorphin cell therapy for cancer prevention. Cancer Prev Res 8(1):56–67

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

    Mojgan Oshaghi & Maryam Roozbehkia

  2. Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Masoumeh Kourosh-Arami

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  1. Mojgan Oshaghi
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Oshaghi, M., Kourosh-Arami, M. & Roozbehkia, M. Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems. Neurol Sci 44, 99–113 (2023). https://doi.org/10.1007/s10072-022-06413-0

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