Mucus overproduction is a major contributor to morbidity and mortality in
asthma. Mucus overproduction is induced by orchestrated actions of multiple factors that include inflammatory
cytokines and γ-
aminobutyric acid (
GABA).
GABA is produced only by pulmonary neuroendocrine cells (PNECs) in the mouse lung. Recent studies in a neonatal mouse model of allergic
inflammation have shown that PNECs play an essential role in mucus overproduction by
GABA hypersecretion. Whether PNECs mediate dysregulated
GABA signaling for mucus overproduction in
asthma is unknown. In this study, we characterized the cellular source of
GABA in the lungs of nonhuman primates and humans and assessed
GABA secretion and signaling in
primate disease models. We found that like in mice, PNECs were the major source of
GABA in primate lungs. In addition, an infant nonhuman primate model of
asthma exhibited an increase in
GABA secretion. Furthermore, subjects with
asthma had elevated levels of expression of a subset of
GABA type α (GABAα) and type β (GABAβ) receptors in airway epithelium compared with those of healthy control subjects. Last, employing a normal human bronchial epithelial cell model of preinduced mucus overproduction, we showed
pharmaceutical blockade of GABAα and GABAβ receptor signaling reversed the effect of
IL-13 on MUC5AC gene expression and goblet cell proliferation. Together, our data demonstrate an evolutionarily conserved intraepithelial
GABA signaling that, in concert with
IL-13, plays an essential role in mucus overproduction. Our findings may offer new strategies to ameliorate mucus overproduction in patients with
asthma by targeting PNEC secretion and
GABA signaling.