Dual activation of estrogen receptor alpha and glucocorticoid receptor upregulate CRTh2‐mediated type 2 inflammation; mechanism driving asthma severity in women?

• Published in: Allergy (Copenhagen) Vol. 78; no. 3; pp. 767 - 779
• Main Authors: Vijeyakumaran, Meerah, Jawhri, MohdWessam Al, Fortunato, Jenna, Solomon, Lauren, Shrestha Palikhe, Nami, Vliagoftis, Harissios, Cameron, Lisa
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.03.2023
• Subjects: Agonists; Annexin V; Apoptosis; Asthma; Asthma - drug therapy; blood serum; CD4 antigen; Cell activation; Cell differentiation; Cell survival; cell viability; eosinophils; estrogen; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Flow cytometry; glucocorticoid; glucocorticoid receptors; Glucocorticoids; Glucocorticoids - therapeutic use; Helper cells; Humans; Inflammation; Inflammation - metabolism; interleukin-13; Interleukin-13 - metabolism; interleukin-5; Leukocytes (eosinophilic); Lymphocytes T; mRNA; Prostaglandin D2 - metabolism; Receptors, Glucocorticoid - metabolism; Receptors, Immunologic - genetics; Receptors, Prostaglandin - genetics; sex differences; Th2 cells; Th2 Cells - metabolism; Western blotting; estrogen; glucocorticoid; asthma; Th2 cells; sex differences
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15543

Background Type 2‐high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant‐homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC). Methods Type 2 inflammation and the proportion of blood Th2 cells (CD4+CRTh2+) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V+, 7‐AAD) were determined by flow cytometry, qRT‐PCR, western blot and ELISA. Results In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL‐13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL‐5 and IL‐13 following CRTh2 activation than Th2 cells treated with GC alone. Conclusion Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production. Th2 cells were higher in women with severe vs mild/moderate asthma and men of either phenotype; Th2 cell numbers correlated with ICS in women, but not men. ERα antagonized GC‐mediated Th2 cell death, increased CRTh2 and reversed GC inhibition of Th2 cytokines induced by PGD2. ERα activation may drive asthma severity in women by interfering with GC.Abbreviations: Th2, T helper 2 cells; ICS, total daily dose of inhaled corticosteroid; GC, glucocorticosteroid; ERα, estrogen receptor alpha; PGD2, prostaglandin D2; CRTh2, chemoattractant receptor‐homologous expressed on Th2 cells.