Novel neuroendocrine role of gamma-aminobutyric acid and gastrin releasing peptide in the host response to influenza infection

Author:

Ann Shirey, Kari

Lai, Wendy

Sunday, Mary

Cuttitta,Frank

Cg Blanco, Jorge

Vogel, Stefanie N
Author Address

Dept. of Microbiology and Immunology, Univ. of Maryland, School of Medicine, Baltimore, MD USA 21201; Senior author., Dept. of Microbiology and Immunology, Univ. of Maryland, School of Medicine, Baltimore, MD USA 21201., Duke University Medical Center, Durham, NC USA 27710., Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD US0041., Sigmovir Biosystems, Inc., Rockville, MD USA 20850.,

Abstract:

Gastrin Releasing Peptide (GRP), an evolutionarily-conserved neuropeptide, significantly contributes to influenza-induced lethality and inflammation in rodent models. Since GRP is produced by pulmonary neuroendocrine cells (PNEC) in response to ?-aminobutyric acid (GABA), we hypothesized that influenza infection promotes GABA release from innervated PNECs that activate GABAB receptors on PNEC to secrete GRP. Oxidative stress was increased in lungs of influenza A/PR/8/34 (PR8)-infected mice, as well as serum glutamate decarboxylase 1 (GAD1), the enzyme that converts L-glutamic acid into GABA. Therapeutic administration of saclofen, a GABAB receptor antagonist, protected PR8-infected mice, reduced lung proinflammatory gene expression of CCR2, CD68, and TLR4, and decreased levels of GRP and HMGB1 in sera. Conversely, baclofen, a GABAB receptor agonist, significantly increased lethality and inflammatory responses. The GRP antagonist, NSC77427, as well as the GABAB antagonist, saclofen, blunted PR8-induced monocyte infiltration into the lung. Together, these data provide the first report of neuroregulatory control of influenza-induced disease. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

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