Christina E Ciaccio, MD, MSc
Assistant Professor of Pediatrics
University of Chicago Medicine
Comer Children’s Hospital
Chicago, Illinois, United States
Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma
Glucocorticoid insensitivity is a therapeutic challenge in severe asthma, and little is known about the mechanisms underlying this problem. This in vitro study of airway smooth muscle cells derived from severe asthmatics proposes one such mechanism. The study recruited 20 patients with severe asthma and 8 healthy controls who underwent bronchoscopy. Chemokines were analyzed, and although no difference was noted between subjects and controls in induced chemokine levels, induction of CCL11 and CCL5 by TNFα was insensitive to dexamethasone or fluticasone in severe asthmatics while induction was dose dependently inhibited in control subjects. Further, investigators found that glucocorticoid receptor nuclear translocation and phosphorylation was impaired in those with severe asthmatics compared to controls, as well as the induction of the GRE-inducible gene, GILZ. Next, investigators showed the PP5, a phosphatase implicated in glucocorticoid signaling, was increased at the transcriptional level and protein level in the airway smooth muscle cells of severe asthmatics compared to controls, and when inhibited by siRNA, cell sensitivity to glucocorticoids was restored. Finally, PP5 was found to be expressed at higher levels in severe asthmatics in vivo via cell staining. The authors, therefore, concluded that in addition to defective glucocorticoid receptor translocation, glucocorticoid insensitivity in severe asthma involves a PP5-dependent suppression of glucocorticoid receptor phosphorylation and transcriptional activities. The novel mechanism offers a new target for therapeutic intervention in severe asthmatics with glucocorticoid insensitivity.
Chachi L, Abbasian M, Gavrila A, Alzahrani A, Tliba O et al. Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma. Allergy 2017; 72(1): 126-136. (doi:10.1111/all.13003)