Post by Kayla Simanek
What's the science?
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. In the central nervous system, GABA signaling imbalance is linked to disorders like epilepsy, anxiety, and schizophrenia. Although it’s role in the central nervous system is well characterized, much less is known about GABA in the immune system. It was recently found that certain immune cells express GABA or GABAergic signaling components, and GABA is now being studied as a potential therapeutic target for chronic inflammation and autoimmune diseases. The impact of GABA signaling on immune defense systems in response to bacterial infections remains unclear. This week in Nature Communications, Kim and colleagues characterize the role of GABA in chronic bacterial infection.
How did they do it?
The authors first determined whether macrophages (peripheral immune cells primarily responsible for “eating” microbial invaders) express GABA in mice. In two macrophage subpopulations (from bone marrow and lung tissue), they measured the electrical current generated by GABA signaling (using patch-clamping) to confirm the expression of functional GABA receptors on these cells. Current amplitude was also measured in mice infected with Mycobacterium tuberculosis (Mtb) or M. bovis (BCG) to determine the level of GABA signaling associated with bacterial infection. Next, the authors tested whether GABAergic signaling promoted responsiveness of the host immune system to bacterial infection. To do this, mice were infected with either Mtb or BCG, treated with GABA and then monitored for changes in immune response compared to an untreated control. Likewise, macrophages isolated from healthy human volunteers were infected with Mtb to determine if the effects of GABA signaling in mice are similar in human immune cells. The gene expression related to autophagy (the “eating” or uptake and killing of intracellular microbes) was analyzed using qRT-PCR in GABA-treated mice to determine whether GABA induced autophagy. Lastly, the authors used drugs that block GABA signaling to study the impact of GABA on macrophage phagosome (a vesicle used to kill bacteria) maturation and the generalized immune response to infection.
What did they find?
The authors found that bone marrow and lung macrophages (i.e. peripheral immune cells) express GABAergic signaling components, as application of GABA invoked inward currents. GABA receptor expression was decreased in mice with bacterial infections, demonstrating that GABA activity is altered by microbial activity. The authors then tested whether activating GABA (using a GABA agonist) or injecting GABA would increase the host defense response to infection. The authors found that GABA activation significantly reduced bacterial burden and lung lesions in infected mice, indicating an increase in host defense mechanisms. They then assessed the mechanism through which this defense occured. They found that GABA treatment induced significant changes in the expression of autophagy-related genes and increased expression of genes involved in the induction of autophagy. After GABA addition or activation, the number of autophagic punctae (indicative of autophagic activity) were also increased, suggesting the activation of autophagy. Further, pathological inflammation (in response to bacterial infection) was reduced by GABA signaling in mice and human cell lines, as the number of pro-inflammatory immune cells and chemicals were decreased. Studies of gene expression showed that GABA increased induction and maturation of the phagosome, ultimately promoting the responsiveness of macrophages to bacterial infection. Blocking GABAergic signaling with drugs (GABA antagonists) nullified this immune responsiveness and increased bacterial growth and lung lesions in infected mice.
What's the impact?
This study found that GABA signaling is not only expressed by immune cells, but vital for immune system responsiveness to bacterial infection. Specifically, macrophage autophagy (the ingesting of pathogenic bacteria) is induced by GABA treatment, or the activation of GABA receptors on immune cells The role of GABA in the immune system was previously unappreciated. GABA has the potential to be a novel target for therapeutic treatment of chronic bacterial infection. This is imperative as the number of antibiotic- and multi-drug resistant bacterial pathogens is increasing.
Kim et al. GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nature Communications (2018). Access the original scientific publication here