Abstract
Asthma is a chronic airway inflammatory disease that affects ~300 million people worldwide. It is characterized by airway constriction that leads to wheezing, coughing, and shortness of breath. The most common treatments are corticosteroids and β2-adrenergic receptor antagonists, which target inflammation and airway smooth muscle constriction, respectively. The incidence and severity of asthma is greater in women than in men, and women are more prone to develop corticosteroid-resistant or “hard-to-treat” asthma. Puberty, menstruation, pregnancy, menopause, and oral contraceptives are known to contribute to disease outcome in women, suggesting a role for estrogen and other hormones impacting allergic inflammation. Currently, the mechanisms underlying these sex differences are poorly understood, although the effect of sex hormones, such as estrogen, on allergic inflammation is gaining interest. Asthma presents as a heterogeneous disease. In typical Th2-type allergic asthma, interleukin (IL)-4 and IL-13 predominate, driving IgE production and recruitment of eosinophils into the lungs. Chronic Th2-inflammation in the lung results in structural changes and activation of multiple immune cell types, leading to a deterioration of lung function over time. Most immune cells express estrogen receptors (ERα, ERβ, or the membrane-bound G-protein-coupled ER) to varying degrees and can respond to the hormone. Together these receptors have demonstrated the capacity to regulate a spectrum of immune functions, including adhesion, migration, survival, wound healing, and antibody and cytokine production. This review will cover the current understanding of estrogen signaling in allergic inflammation and discuss how this signaling may contribute to sex differences in asthma and allergy.
Highlights
ON ALLERGIC INFLAMMATION AND ASTHMAAllergic disorders are characterized by Th2 responses against innocuous environmental factors that result in eosinophilic inflammation and the production of interleukin (IL)-4, IL-13, and IgE
Adult asthma is clinically dominated by women, and the contribution of estrogen to this sex difference is becoming clear
It is imperative that the several different endotypes that comprise asthma be fully characterized and suited with appropriate rodent and in vitro models that will enable us to address potential therapeutic avenues
Summary
Allergic disorders are characterized by Th2 responses against innocuous environmental factors that result in eosinophilic inflammation and the production of interleukin (IL)-4, IL-13, and IgE. ER signaling is regulated by several factors, including the relative abundance of receptor isoforms, interactions with coactivators/corepressors, and DNA-remodeling proteins, receptor phosphorylation, and inputs from other signaling networks This variety in regulation permits profound functional versatility and provides an avenue for hormonal influence over many biological pathways and processes, like allergic inflammation. The production of lipid inflammatory mediators like leukotrienes via 5-lipoxygenase is enhanced in female leukocytes compared to that in male leukocytes, but this difference is due to suppression of the pathway by testosterone [99] This central role of macrophages in allergic lung inflammation has warranted studies addressing the potential influence of sex hormones on macrophage polarization and inflammatory cytokine production.
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