The gamma‐aminobutyric acid (GABA)A receptor modulates the cytokine response to rhinovirus exposure in human monocytic cells

Abstract

Rhinoviral infections are a major cause of asthma exacerbations. Though productive rhinovirus infections occur predominantly in the bronchial epithelial cells of the upper airway, monocytic‐lineage cells, the most prominent immune cell in the lung, are important in establishing the inflammatory microenvironment observed during rhinoviral asthma exacerbations. Emerging evidence indicates that the gamma‐aminobutyric acid type A receptor (GABAAR) signaling system on leukocytes, airway epithelial cells and airway smooth muscle cells modulates the inflammation in the lung. We sought to determine if GABAAR signaling alters the release of inflammatory mediators from human monocyte‐derived macrophages (MDM) exposed to human rhinovirus (HRV). Results demonstrate that GABAARs on human MDMs are functional and stimulation with GABA or HRV caused GABAARs on the cell surface undergo protein kinase C (PKC)‐mediated endocytic removal and recycling, similar to that found in neurons. GABA treatment of MDMs during HRV exposure attenuated the production of HRV stimulated CCL2 and CXCL10 production by inhibiting the stress kinase June N‐terminal kinase (JNK) and increasing phosphorylation of extracellular regulated kinase (ERK). Interestingly, GABA stimulated the production of interferon‐b through the classical innate immune signaling molecules TANK binding kinase (TBK) and interferon regulated factor 3 (IRF3). Phosphorylation TBK occurred via the lysine deficient kinase (WNK) pathway after the influx of chloride ions when GABAARs are stimulated. Our findings suggest that GABA treatment of MDMs lead to a novel activation of the WNK‐TBK‐IRF3 axis implying the potential for GABA‐mediated treatment of HRV‐induced asthma exacerbations.Support or Funding InformationLawrence University, NIH grant R15 AI065505‐01A1 and NSF grant 0521112.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.