Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Sep 27, 2020; 11(2): 30-51
Published online Sep 27, 2020. doi: 10.4331/wjbc.v11.i2.30
Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity
Indiwari Gopallawa, Robert J Lee
Indiwari Gopallawa, Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
Robert J Lee, Department of Otorhinolaryngology and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
Author contributions: Gopallawa I drafted and wrote the entire paper; Lee RJ revised and edited the manuscript.
Supported by The United States National Institutes of Health, No. R01DC016309; The United States Cystic Fibrosis Foundation, No. GOPALL19F0.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Robert J Lee, PhD, Assistant Professor, Department of Otorhinolaryngology and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5th Floor Ravdin, Suite A, Philadelphia, PA 19104, United States. rjl@pennmedicine.upenn.edu
Received: June 17, 2020
Peer-review started: June 17, 2020
First decision: July 21, 2020
Revised: July 24, 2020
Accepted: August 25, 2020
Article in press: August 25, 2020
Published online: September 27, 2020
Abstract

The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens via activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens via mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.

Keywords: Lung, Nitric oxide synthase, Nuclear factor erythroid 2 related factor-2, Respiratory infections, Cystic fibrosis

Core Tip: The human respiratory epithelium is continuously exposed to pathogens during each inhalation. Protection of the lung depends on complex signaling networks that activate host defense mechanisms. The kinase protein kinase B (Akt) interacts with numerous cellular proteins involved in airway innate immunity. In this review, we discuss the Akt pathway and known downstream targets involved in airway innate immunity.