Glucocorticoid Insensitivity in Severe Asthma: Underlying Molecular Mechanisms, Challenges, and Emerging Therapies

Glucocorticoids are the cornerstone of asthma therapy due to their potent anti-inflammatory action. However, a subset of severe asthmatics do not respond to the standard glucocorticoid treatment. Such phenomenon is referred to as glucocorticoid insensitivity (GCI). From a clinical point of view, GCI is characterized by the reduced therapeutic response with improvement of less than 10-15% in lung function parameters, such as FEV1, upon the administration of an adequate glucocorticoid dose. The mechanisms underlying GCI involve disrupted glucocorticoid receptor (GR) signaling, overexpression of the dominant-negative GRβ isoform, increased activity of pro-inflammatory transcription factors such as NF-κB and AP-1, and abnormal GR phosphorylation by kinases such as p38 MAPK. These altered molecular pathways undermine the anti-inflammatory effects of glucocorticoids on immune and structural airway cells, thus maintaining the chronicity of airway inflammation and remodeling. GCI can be of innate genetic origin, as in the case of GR mutations, or acquired through environmental exposures, including viral infections, smoking, and long-term exposure to pollutants in the environment. GCI represents a big challenge in the management of asthma, since a large proportion of cases do not achieve an adequate level of control with the standard treatment options. Recent advances in the understanding of the molecular mechanisms underlying GCI have enabled the development of novel therapeutic strategies, including biologic therapies targeting interleukin-5 and IL-13, Janus kinase inhibitors, and small-molecule drugs aimed at restoring GR function. This article presents a critical discussion on the current state of knowledge regarding the glucocorticoid resistance mechanisms in asthma, identifying the clinical effects of new therapeutic strategies, with special emphasis on the need for personalized treatment regimens to improve outcomes in glucocorticoid insensitivity.