Review articles (listed chronologically) that summarize effects of β2-AR/cAMP signaling on neutrophils.
| Source | Stimulus | Phenotype |
|---|---|---|
| Marino and Cosentino, 2013; Scanzano and Cosentino, 2015 | β2-AR agonists/cAMP | Exert an anti-inflammatory effect on neutrophils, reducing ROS production and migration and blunting adhesion of neutrophils to the endothelium. Anti-inflammatory effects of β2-AR on neutrophils may decrease with age. Some evidence suggests that neutrophils produce catecholamines, creating autocrine feedback loops. |
| Theron et al., 2013 | β2-AR agonists/cAMP | Reduce production/release of ROS, LTB4, CR3, and IL-8. Decrease chemotaxis and adhesion to epithelia. Modulate neutrophil hyperreactivity by regulating cytosolic Ca2+ fluxes through multiple complementary mechanisms. cAMP/CREB signaling in neighboring immune cells (DCs, macrophages, etc.) that increase IL-10 release can regulate responses of neutrophils. cAMP/PKA signaling likely improves anti-inflammatory effects of corticosteroids by inhibiting mechanisms of corticosteroid resistance. PDE4 is the most important cAMP-selective PDE in neutrophils; PDE4 inhibitors (e.g., roflumilast) hypothesized to have anti-inflammatory effects. |
| Kolmus et al., 2015 | β2-AR–mediated inhibition of NF-κB signaling | β2-AR agonists decease NF-κB activity in neutrophils, thereby reducing IL-8 production. |
| Raker et al., 2016 | cAMP/PDE inhibitors | Reduce NET formation; NETs can mediate neutrophil actions and are used by certain organisms for immune evasion. |
| Arumugham et al., 2017 | cAMP, PKA, and EPAC | cAMP via PKA has inhibitory effects on neutrophil function (migration, phagocytosis), but EPAC1 has opposite effects. |
| Li et al., 2018 | Regulation of cAMP signaling by PDEs | PDE4 inhibitors have anti-inflammatory effects on neutrophils, including reduced activation, production of ROS and LTB4, production/release of inflammatory cytokines, and inhibition of chemotaxis/infiltration. Inhaled PDE4 inhibitors can reduce inflammation in models of pulmonary neutrophilia. |
| Fessler, 2019; Dunne et al., 2019 | Regulation of cAMP signaling by PDEs | PDE4 inhibition exerts anti-inflammatory effects, e.g., reduced neutrophil chemotaxis by increasing EPAC1 activity. Neutrophils from patients with COPD are highly chemotactic and can be inhibited by PDE4 inhibition. Prior data indicated that a PDE4 inhibitor reduces neutrophil number and inflammatory markers in sputum of patients with COPD (Grootendorst et al., 2007). |
| Tavares et al., 2020 | cAMP, PKA, and EPAC | Increased cAMP in neutrophils reduces chemotaxis, ROS production, NET formation, phagocytosis, and killing of pathogens. cAMP/PKA exert complex effects on neutrophil apoptosis; PKA activation increases apoptosis, including in LPS-stimulated neutrophils, with inhibition of prosurvival proteins (AKT, NF-κB) and increase of proapoptotic proteins. Other studies show the reverse in neutrophils ex vivo, perhaps through PKA-independent mechanisms (Martin et al., 2001). Thus, the net effect of cAMP on neutrophil apoptosis is unclear. |
CR3, Complement receptor 3; LTB4, Leukotriene B4.