Dual Activation of Estrogen Receptor Alpha and Glucocorticoid Receptor
Upregulate CRTh2-Mediated Type 2 Inflammation; Mechanism Driving Asthma
Severity in Women?
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