Introduction
Asthma is a chronic inflammatory disease affecting approximately 300
million people worldwide [1]. Asthma
symptoms can range from mild and manageable on low dose inhaled
corticosteroids (CS) to severe and uncontrolled despite intense
treatment [2]. Attempts to understand
this heterogeneity have led to phenotyping asthma according to clinical,
physiologic and cellular phenomena [3]
and ultimately to efforts to determine the molecular mechanisms, or
endotypes, driving disease [4].
Currently, at least two endotypes of severe asthma have been identified;
patients exhibiting persistent type 2 inflammation with eosinophilia
(type 2-high) and those with type 1/type 17 inflammation with
neutrophilia (type 2-low) [3].
Type 2-high asthma is characterized by increased numbers of blood and
airway Th2 cells, eosinophils, group 2 innate lymphoid cells (ILC2) and
type 2 cytokines IL-4, IL-5 and IL-13
[3, 4].
Woodruff et al. examined bronchial biopsies from mild-moderate
asthmatics and healthy controls and showed that patients with high
expression of type 2 cytokines improved following inhaled CS (ICS)
treatment [5]. In type 2-high severe
asthma, however, symptoms and inflammation persist despite high dose
inhaled and/or oral CS [6,
7]. Though anti-type 2 therapies are
effective in these patients, indicating the pathway mediates their
symptoms [2], the mechanism(s) driving
persistence of type 2 inflammation remain elusive.
Expression of CRTh2 (chemoattractant-homologous receptor expressed on
Th2 cells) by CD4+ T cells is considered a marker of
Th2 cells [8-10], but CRTh2 is also
expressed by eosinophils, basophils, ILC2 and some
CD8+ T cells
[10-12]. CRTh2 is a receptor for
prostaglandin D2 (PGD2), a lipid
mediator released by mast cells within the airways following
allergen-induced activation [13-15].
PGD2 activation of CRTh2 regulates Th2 cell function
mediating chemotaxis, type 2 cytokine expression and inhibition of
apoptosis [10,
13, 16,
17]. In murine models of asthma, CRTh2
deficiency reduced eosinophil infiltration and IL-5 production within
the lung [18,
19]. Administration of CRTh2
antagonists or depleting antibodies also showed a reduction in airway
hyper-reactivity, serum IgE levels, mucus secretion and leukocyte
infiltration into the airways [18,
20, 21].
CD4+CRTh2+ T cells (i.e. Th2
cells) circulating within the blood have a memory phenotype and their
frequency is considered to influence one’s susceptibility to respond to
subsequent allergen exposures [9,
22-24]. Although severe asthmatics have
been shown to have higher levels of Th2 cells, CRTh2 mRNA and
PGD2 in the blood and airways
[25,
26], whether this pathway influences
Th2 cell response to CS and/or plays a role in persistence of type 2
inflammation has not been examined.
Women are more likely to be diagnosed with severe asthma
[27], to have severe exacerbations
requiring hospitalization [28] and to
relapse following treatment for exacerbation
[29]. Serum estrogen levels have been
associated with amount of IL-5 in sputum of women reporting
peri-menstrual asthma symptoms [30].
CD4+ T cells express estrogen receptors (ER)
[31] and in a mouse model of asthma
estrogen administration induced expression of type 2 cytokines
[32] through ER alpha (ERα)
activation [33]. Here we examined the
relationship between asthma severity and type 2 inflammation in a
sex-stratified analysis and assessed the ability of estrogen receptor
signaling to influence Th2 cell response to in vitro exposure to
CS.