Inhibitory role for GABA in autoimmune inflammation.
GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.
Bhat
Roopa
R
Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305, USA. roopa.bhat@stanford.edu
Axtell
Robert
R
Mitra
Ananya
A
Miranda
Melissa
M
Lock
Christopher
C
Tsien
Richard W
RW
Steinman
Lawrence
L
D000612:4-Aminobutyrate Transaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D018682:GABA Agents / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D018408:Patch-Clamp Techniques; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
D018682:GABA Agents; D050485:GABA Plasma Membrane Transport Proteins; D020381:Interleukin-17; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D007371:Interferon-gamma; D000612:4-Aminobutyrate Transaminase