The molecular mechanisms of glucocorticoids-mediated neutrophil survival

Abstract

Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.

Fig. (1). A schematic model of glucocorticoid induced survival of human neutrophil.

Following treatment of neutrophils with dexamethasone, the latter binds to GR inducing release of the receptor from its protein complex, dimerization and translocation to the nucleus where it can up regulate Mcl-1 and XIAP expression. The net effects are maintenance of mitochondrial integrity and suppression of caspases. GR also modulates P38 and PI3K activation that may influence Mcl-1 expression or function.