Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis

Abstract

Current treatments for rheumatoid arthritis (RA) have long-term side effects such that new treatments are needed that can safely help manage the disease. There is a growing appreciation that GABA receptors (GABA-Rs) on immune cells provide new targets that can be used to modulate immune cell activity. Here, we show for the first time that activation of peripheral GABA-Rs can inhibit the development of disease in the collagen-induced arthritis (CIA) mouse model of RA. Mice that received oral GABA had a reduced incidence of CIA, and those mice that did develop CIA had milder symptoms. T cells from GABA-treated mice displayed reduced proliferative responses to collagen and their APC had a reduced ability to promote the proliferation of collagen-reactive T cells. Thus, GABA downregulated both T-cell autoimmunity and APC activity. Collagen-reactive T cells from GABA-treated mice displayed reduced recall responses in the presence of GABA ex vivo, indicating that GABA consumption did not desensitize these cells to GABA. GABA-treated mice had reduced collagen-reactive IgG2a, but not IgG1 antibodies, consistent with reduced Th1 help. The levels of serum anti-collagen IgG2a antibodies were correlated significantly with the CIA disease scores of individual mice. Our results suggest that activation of peripheral GABA-Rs may provide a new modality to modulate T cell, B cell, and APC activity and help ameliorate RA and other inflammatory diseases.

Immunological GABAergic interactions and therapeutic applications in autoimmune diseases

“…Tian et al [61] showed that activation of peripheral GABA receptors ameliorates this disease in mice. The T cells of mice treated with GABA displayed reduced proliferative responses to collagen, and their APCs reduced stimulatory capacity.…”

GABA Is an Effective Immunomodulatory Molecule in the Brain and in the Periphery

“…When GABA opens the GABA-A channels in the immune cells' plasma membrane, the membrane potential will change and can thereby affect a number of cellular processes including the entry of calcium into the cell by decreasing the driving force on the calcium ion ( Fig. 5.2 (Bhat and Steinman 2009;Mendu et al 2011;Soltani et al 2011;Tian et al 2011;Wheeler et al 2011). Neuroinflammation is also involved in epileptogenic processes in the brain (for review see Vezzani et al 2008) where infiltration of leukocytes into the brain (Fabene et al 2008;Zattoni et al 2011) and increased production of pro-inflammatory cytokines (Li et al 2011) have been shown to be associated with the induction and progression of epilepsy.…”

“…GABA is decreased in serum of MS patients (Demakova et al 2003), oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis (Tian et al 2011), disregulation of GABA metabolism precedes pancreatic islets autoimmunity in children who later progress to type 1 diabetes (Oresic et al 2008) and GAD is a major autoantibody in type 1 diabetes (Lernmark et al 1978). What role the GABA system has in these diseases remains nevertheless to be clarified.…”

“…Similarly, in 2010 Bath et al (2010) showed that increasing the GABAergic activity ameliorated ongoing paralysis in EAE, the mouse model for multiple sclerosis, via inhibition of inflammation. GABA has also been proposed to have a role in rheumatoid arthritis (Kelley et al 2008;Tian et al 2011) and psoriasis (Nigam et al 2010).…”

GABA and Topiramate Inhibit the Formation of Human Macrophage-Derived Foam Cells by Modulating Cholesterol-Metabolism-Associated Molecules

“…GABA acts on GABA receptors to affect a variety functional properties of the immune cells, such as cytokine secretion, cell proliferation, phagocytic activity and chemotaxis [10,11]. Increasing GABAergic activity ameliorates the progression of autoimmune diseases, such as multiple sclerosis, diabetes mellitus and rheumatoid arthritis [12,13,14,15]. …”