Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

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.

Small-molecule Akt-activation in airway cells induces NO production and reduces IL-8 transcription through Nrf-2

“…6 c). This is consistent with other studies showing Nrf-2 reduces inflammation in animal models [ 17 ]. A concentration of brusatol below the threshold able to degrade Nrf-2 (1 nM; consistent with other studies [ 36 ]) was not sufficient to increase IL-8 levels [ 37 ] (Fig.…”

“…Dysfunctional Nrf-2 may contribute to hyperinflammation observed in CF airway epithelial cells [ 17 ]. We hypothesized that direct Akt activation may increase Nrf-2 protein in airway epithelial cells.…”

“…Pharmacological studies have suggested anti-inflammatory cross-talk between Nrf-2 and NF-κB pathways, although the exact dynamics of this cross-talk is yet to be elucidated [ 17 ]. In endothelial cells, induction of HO-1 inhibited NF-κB-mediated transcription of adhesion molecules such as vascular cell adhesion molecule-1 and E-Selectin [ 51 ].…”

“…Another downstream effector that may make Akt-targeting beneficial is nuclear factor erythroid 2–related factor 2 (Nrf-2) [ 17 ]. Nrf-2 is a transcription factor that resides in the cytosol and is negatively regulated by kelch-like ECH-associated protein-1 (KEAP-1).…”

TACSTD2 upregulation is an early reaction to lung infection

“…Activation of the Akt kinase signaling by Trop2 upregulation in response to infection may therefore enhance lung cell survival and decrease tissue damage. It should be noted, however, that controversial role of Akt kinase in modulating infection and inflammation in lungs has been reported(58,59) vs(60)(61)(62)(63). Interestingly, both Trop2related functional targets, tight junctions proteins and Akt kinase, were reported to be hijacked by diverse viruses to promote their infection in various tissues.…”