Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter of the brain, playing an essential role in balancing neuronal excitatory and inhibitory activity. GABA is produced in peripheral tissues, including the pancreas, pituitary, and gastrointestinal tract [1], and, interestingly, in immune cells, expressing GABA receptors and transporters [2]. Consequently, GABA plays a role in the central nervous system (CNS), peripheral tissues, and, more interestingly, the immune system, which exerts other biological functions [3].
The immune system mediates complex responses to fight against infection via various immune cells derived from progenitor stem cells in the bone marrow. The myeloid lineages involve monocytes, dendritic cells, macrophages, and granulocytes, while the lymphoid lineages involve lymphocytes B, lymphocytes T, and natural killer cells [4]. The innate response is immediate and our first line of defense. The adaptive immune response, more specific and long-lasting, is our second line of defense. Evidence demonstrates that neurotransmitters, such as acetylcholine [5], and GABA [2], modulate immune cells. This article reports the recent findings connecting GABA to the immune system through its interactions with various immune cells.
Immune cells and GABAergic signaling
Mononuclear phagocytes
Mononuclear phagocytes, including dendritic cells, monocytes, macrophages, and microglia in the CNS, are crucial players in the fight against microbial infection. The phagocyte pathogens participate in cytokine secretion and antigenic presentation to initiate the adaptive immune response. Mononuclear phagocytes express GAD-67, the 67 kDa isoform of the GABA-synthesizing enzyme. Upon infection, GAD67 expression increases, indicating GABA synthesis and extracellular GABA concentrations rise dramatically [6]. Phagocytes also express pentametric GABA-A receptors, although their precise subunit constituents remain unknown, and cation-chloride cotransporters, including the Na–K–Cl cotransporter NKCC1, regulating GABA-A receptors via modulating intracellular chloride. Finally, mononuclear phagocytes express the voltage-dependent calcium (Ca2+) channels (VDCCs), which open after GABA-A receptors activation by GABA and elicit Ca2+ influx within the cells [6].
Experiments in mice showed that infection with coccidian parasites activated the GABAergic system of phagocytes, enhancing their motility in vitro and their migratory responses in vivo. Evidence from selective pharmacological antagonists and gene silencing experiments demonstrated that GABA-A receptors (especially subunits α4, β3, and ρ), NKCC1, and VDCCs are essential for phagocytes’ motility [6]. GABAergic signaling is also involved in the movement of dendritic cells in response to chemokines CCL19/21 gradient (chemotactic response) [7,8]. Indeed, upon GABAergic inhibition, the movements of dendritic cells are much slower, reducing the global chemotactic response [9,10].
T lymphocytes
T lymphocytes are involved in the adaptive immune responses and provide long-lasting immunity. There are four types of T lymphocytes: cytotoxic T cells (CD8+ T cells), helper T cells (CD4+ helper T cells), regulatory T cells, and memory T cells. T lymphocytes express GAD67, two GABA transporters (GAT1 and GAT2), the enzyme responsible for its catabolism (GABA transaminase or GABA-T), and GABA-A receptors. The expression of the GABA-A receptor and its subunit composition vary depending on the species, activation of the cells, and type of experiments [11]. Different T cells display GABA-A receptors composed of different subunits, resulting in various pharmacological properties and effects [2,12]. GABA binding to functional GABA-A receptors on T cells suppresses proliferation and inhibits the immune response [13-15]. In addition, gene silencing of NKCC1 inhibits the migration and chemotaxis of T cells in mice [16].
Natural killer cells
Natural killer (NK) cells exert cytotoxic effects on target cells through perforin-dependent mechanisms or inducing death receptor-mediated apoptosis. They play an essential role in immunomodulation with cytokines secretions and regulate T-cell-mediated responses [17].
Human NK cells express GAD67, GABA-T, GAT2, diverse subunits of the GABA-A receptor (most commonly α3, β2, and ρ2 subunits), and NKCC1 [18]. Concomitant expression of GAT2 and GAD67 suggests that GABA is synthesized in the cytosol before secretion in vesicles, as observed in neurons [19,20]. Upon infection, the GAD67 gene is up-regulated while the GABA-T gene is down-regulated in humans, demonstrating a tightly regulated GABA production in NK cells. In vitro, upon challenge with Toxoplasma gondii, parasitized NK cells secrete GABA, which impedes their cytotoxicity and degranulation [18]. However, GABA’s effects on NK cells remain unclear [21].
B lymphocytes and granulocytes
B lymphocytes (or B cells) and granulocytes, including neutrophils, eosinophils, basophils, and mast cells, are involved in adaptive and innate immune responses, respectively. B cells express subunits of the GABA-A receptor, as demonstrated by western blot analysis of human B-cell lysates and mRNA amplification [22]. GABA-A receptors are involved in neutrophil chemotaxis and recruitment to inflammatory sites [23,24]. Neutrophils express GABA-A and GABA-B receptors, and type B receptors can stimulate neutrophil chemotaxis [25]. Yet, GABA signaling in those cells needs further research.
GABA signaling as a therapeutic target in autoimmune diseases and inflammation
Type 1 diabetes
Type 1 diabetes (T1D) is an autoimmune disease in which T-cells infiltrate the islets of Langerhans of the pancreas to destroy the beta-cells producing insulin. As a result, insulin production declines slowly, resulting in glycemia dysregulation. In non-obese diabetic mice, oral or intra-peritoneal administration of GABA demonstrated protective effects against T1D. In vitro, 100 μM of GABA suppressed activated T-cell responses against beta-cells. Another experiment involving prediabetic mice demonstrated that GABA protects against T1D development [26]. T1D development also involves inflammatory mechanisms, and anti-inflammatory therapy demonstrated protective effects in mice receiving multiple low doses of streptozotocin to induce diabetes [27]. In this model, GABA treatment reduced serum levels of inflammatory cytokines, including IL-1β, IL-12, TNF-α, and IFN-γ [28].
Dermatitis
Modulation of GABA signaling may be beneficial in several forms of dermatitis. In a mouse model of allergic contact dermatitis, baclofen, a GABA-B receptor agonist, alleviated signs of inflammation and reduced the recruitment of neutrophils, monocytes, and lymphocytes into mice skin [29]. In patients with psoriasis, immune cells expressing GABA-A receptors are present in skin lesions [30]. A case report described beneficial effects on psoriasis in one patient treated with GABA analogs (gabapentin and pregabalin) [31]. Both analogs also appear effective in managing pruritus [32,33].
Conclusion
Recent evidence highlights the importance of the GABAergic system for the immune system. The presence of GABA, along with its synthesizing enzyme, catabolic enzyme, transporters, and receptors in immune cells, has opened a new field of study. It is a promising area for future drug development. GABAergic drugs might be effective in treating autoimmune diseases, such as T1D. Results in animal models are impressive; however, clinical literature is minimal, and prospective clinical trials are needed to assess the immunological effects of treatment with GABA or its analogs [3].
If you're interested in learning about some ways to boost your immune system, you can read more about herbs to boost your immune system here or supplements to boost your immune function here. You can also see the impact of diet and nutrition on your immune system here or learn about some laboratory tests to assess your immune function here.
References
[1] Gladkevich, A., Korf, J., Hakobyan, V.P. and Melkonyan, K.V. (2006) The peripheral GABAergic system as a target in endocrine disorders. Autonomic Neuroscience, 124, 1–8. https://doi.org/10.1016/j.autneu.2005.11.002
[2] Jin, Z., Mendu, S.K. and Birnir, B. (2013) GABA is an effective immunomodulatory molecule. Amino Acids, 45, 87–94. https://doi.org/10.1007/s00726-011-1193-7
[3] Prud’homme, G.J., Glinka, Y. and Wang, Q. (2015) Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmunity Reviews, 14, 1048–56. https://doi.org/10.1016/j.autrev.2015.07.011
[4] Laurenti, E. and Göttgens, B. (2018) From haematopoietic stem cells to complex differentiation landscapes. Nature, 553, 418–26. https://doi.org/10.1038/nature25022
[5] Olofsson, P.S., Rosas‐Ballina, M., Levine, Y.A. and Tracey, K.J. (2012) Rethinking inflammation: neural circuits in the regulation of immunity. Immunological Reviews, 248, 188–204. https://doi.org/10.1111/j.1600-065X.2012.01138.x
[6] Bhandage, A.K., Olivera, G.C., Kanatani, S., Thompson, E., Loré, K., Varas-Godoy, M. et al. (2020) A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites. eLife, 9, e60528. https://doi.org/10.7554/eLife.60528
[7] Fuks, J.M., Arrighi, R.B.G., Weidner, J.M., Kumar Mendu, S., Jin, Z., Wallin, R.P.A. et al. (2012) GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii. Hunter CA, editor. PLoS Pathogens, 8, e1003051. https://doi.org/10.1371/journal.ppat.1003051
[8] Weidner, J.M., Kanatani, S., Hernández-Castañeda, M.A., Fuks, J.M., Rethi, B., Wallin, R.P.A. et al. (2013) Rapid cytoskeleton remodelling in dendritic cells following invasion by Toxoplasma gondii coincides with the onset of a hypermigratory phenotype: Toxoplasma -induced migratory activation of DC. Cellular Microbiology, n/a-n/a. https://doi.org/10.1111/cmi.12145
[9] Ólafsson, E.B., Ross, E.C., Varas-Godoy, M. and Barragan, A. (2019) TIMP-1 promotes hypermigration of Toxoplasma -infected primary dendritic cells via CD63–ITGB1–FAK signaling. Journal of Cell Science, 132, jcs225193. https://doi.org/10.1242/jcs.225193
[10] Ólafsson, E.B., Ten Hoeve, A.L., Li Wang, X., Westermark, L., Varas-Godoy, M. and Barragan, A. (2020) Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma -infected dendritic cells. Journal of Cell Science, jcs.241752. https://doi.org/10.1242/jcs.241752
[11] Barragan, A., Weidner, J.M., Jin, Z., Korpi, E.R. and Birnir, B. (2015) GABA ergic signalling in the immune system. Acta Physiologica, 213, 819–27. https://doi.org/10.1111/apha.12467
[12] Birnir, B. and Korpi, E. (2007) The Impact of Sub-Cellular Location and Intracellular Neuronal Proteins on Properties of GABAA Receptors. Current Pharmaceutical Design, 13, 3169–77. https://doi.org/10.2174/138161207782341330
[13] Bhandage, A.K., Jin, Z., Korol, S.V., Shen, Q., Pei, Y., Deng, Q. et al. (2018) GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes. eBioMedicine, 30, 283–94. https://doi.org/10.1016/j.ebiom.2018.03.019
[14] Tian, J., Chau, C., Hales, T.G. and Kaufman, D.L. (1999) GABAA receptors mediate inhibition of T cell responses. Journal of Neuroimmunology, 96, 21–8. https://doi.org/10.1016/S0165-5728(98)00264-1
[15] Prud’homme, G.J., Glinka, Y., Hasilo, C., Paraskevas, S., Li, X. and Wang, Q. (2013) GABA Protects Human Islet Cells Against the Deleterious Effects of Immunosuppressive Drugs and Exerts Immunoinhibitory Effects Alone. Transplantation, 96, 616–23. https://doi.org/10.1097/TP.0b013e31829c24be
[16] Köchl, R., Thelen, F., Vanes, L., Brazão, T.F., Fountain, K., Xie, J. et al. (2016) WNK1 kinase balances T cell adhesion versus migration in vivo. Nature Immunology, 17, 1075–83. https://doi.org/10.1038/ni.3495
[17] Kadri, N., Wagner, A.K., Ganesan, S., Kärre, K., Wickström, S., Johansson, M.H. et al. (2015) Dynamic Regulation of NK Cell Responsiveness. In: Vivier E, Di Santo J, and Moretta A, editors. Natural Killer Cells, Springer International Publishing, Cham. p. 95–114. https://doi.org/10.1007/82_2015_485
[18] Bhandage, A.K., Friedrich, L.M., Kanatani, S., Jakobsson-Björkén, S., Escrig-Larena, J.I., Wagner, A.K. et al. (2021) GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii. Journal of Leukocyte Biology, 110, 617–28. https://doi.org/10.1002/JLB.3HI0720-431R
[19] Kaufman, D.L., Houser, C.R. and Tobin, A.J. (1991) Two Forms of the γ‐Aminobutyric Acid Synthetic Enzyme Glutamate Decarboxylase Have Distinct Intraneuronal Distributions and Cofactor Interactions. Journal of Neurochemistry, 56, 720–3. https://doi.org/10.1111/j.1471-4159.1991.tb08211.x
[20] Feldblum, S., Erlander, M.G. and Tobin, A.J. (1993) Different distributions of GAD65 and GAD67 mRNAS suggest that the two glutamate decarboxylases play distinctive functional roles. Journal of Neuroscience Research, 34, 689–706. https://doi.org/10.1002/jnr.490340612
[21] Lang, K., Drell, T.L., Niggemann, B., Zänker, K.S. and Entschladen, F. (2003) Neurotransmitters regulate the migration and cytotoxicity in natural killer cells. Immunology Letters, 90, 165–72. https://doi.org/10.1016/j.imlet.2003.09.004
[22] Alam, S., Laughton, D.L., Walding, A. and Wolstenholme, A.J. (2006) Human peripheral blood mononuclear cells express GABAA receptor subunits. Molecular Immunology, 43, 1432–42. https://doi.org/10.1016/j.molimm.2005.07.025
[23] Rane, M.J., Gozal, D., Butt, W., Gozal, E., Pierce, W.M., Guo, S.Z. et al. (2005) γ-Amino Butyric Acid Type B Receptors Stimulate Neutrophil Chemotaxis during Ischemia-Reperfusion. The Journal of Immunology, 174, 7242–9. https://doi.org/10.4049/jimmunol.174.11.7242
[24] Bassi, G.S., Do C. Malvar, D., Cunha, T.M., Cunha, F.Q. and Kanashiro, A. (2016) Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis. Naunyn-Schmiedeberg’s Archives of Pharmacology, 389, 851–61. https://doi.org/10.1007/s00210-016-1248-0
[25] Steinman, R.M. and Banchereau, J. (2007) Taking dendritic cells into medicine. Nature, 449, 419–26. https://doi.org/10.1038/nature06175
[26] Tian, J., Lu, Y., Zhang, H., Chau, C.H., Dang, H.N. and Kaufman, D.L. (2004) γ-Aminobutyric Acid Inhibits T Cell Autoimmunity and the Development of Inflammatory Responses in a Mouse Type 1 Diabetes Model. The Journal of Immunology, 173, 5298–304. https://doi.org/10.4049/jimmunol.173.8.5298
[27] Cockfield, S.M., Ramassar, V., Urmson, J. and Halloran, P.F. (1989) Multiple low dose streptozotocin induces systemic MHC expression in mice by triggering T cells to release IFN-gamma. The Journal of Immunology, 142, 1120–8. https://doi.org/10.4049/jimmunol.142.4.1120
[28] Soltani, N., Qiu, H., Aleksic, M., Glinka, Y., Zhao, F., Liu, R. et al. (2011) GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proceedings of the National Academy of Sciences, 108, 11692–7. https://doi.org/10.1073/pnas.1102715108
[29] Duthey, B., Hübner, A., Diehl, S., Boehncke, S., Pfeffer, J. and Boehncke, W. (2010) Anti‐inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis. Experimental Dermatology, 19, 661–6. https://doi.org/10.1111/j.1600-0625.2010.01076.x
[30] Nigam, R., El-Nour, H., Amatya, B. and Nordlind, K. (2010) GABA and GABAA receptor expression on immune cells in psoriasis: a pathophysiological role. Archives of Dermatological Research, 302, 507–15. https://doi.org/10.1007/s00403-010-1052-5
[31] Boyd, S.T., Mihm, L. and Causey, N.W. (2008) Improvement in Psoriasis following Treatment with Gabapentin and Pregabalin: American Journal of Clinical Dermatology, 9, 419. https://doi.org/10.2165/0128071-200809060-00012
[32] Lee, J., Jang, D., Bae, J., Jung, H., Park, M. and Ahn, J. (2020) Efficacy of pregabalin for the treatment of chronic pruritus of unknown origin, assessed based on electric current perception threshold. Scientific Reports, 10, 1022. https://doi.org/10.1038/s41598-020-57629-z
[33] Xu, W., Dong, H., Ran, H., Liu, H., Wang, L., Li, H. et al. (2025) Efficacy and Safety of Pregabalin and Gabapentin for Pruritus: A Systematic Review and Meta-Analysis. Journal of Pain and Symptom Management, Elsevier. 69, 65–81. https://doi.org/10.1016/j.jpainsymman.2024.08.028
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