Sex Plays a Multifaceted Role in Asthma Pathogenesis

Abstract

Sex is considered an important risk factor for asthma onset and exacerbation. The prevalence of asthma is higher in boys than in girls during childhood, which shows a reverse trend after puberty-it becomes higher in adult females than in adult males. In addition, asthma severity, characterized by the rate of hospitalization and relapse after discharge from the emergency department, is higher in female patients. Basic research indicates that female sex hormones enhance type 2 adaptive immune responses, and male sex hormones negatively regulate type 2 innate immune responses. However, whether hormone replacement therapy in postmenopausal women increases the risk of current asthma and asthma onset remains controversial in clinical settings. Recently, sex has also been shown to influence the pathophysiology of asthma in its relationship with genetic or other environmental factors, which modulate asthmatic immune responses in the airway mucosa. In this narrative review, we highlight the role of sex in the continuity of the asthmatic immune response from sensing allergens to Th2 cell activation based on our own data. In addition, we elucidate the interactive role of sex with genetic or environmental factors in asthma exacerbation in women.

Keywords: airway epithelial cells; bronchial asthma; cluster of differentiation 8+ T cells; dendritic cells; eosinophils; estradiol; psychological stress; respiratory tract infection; sex; single nucleotide polymorphism.

Figure 1

Sex-based differences in airway epithelial cell function. (A) Sex differences in Il33 and Ccl2 mRNA levels in Ep-CAM⁺ airway epithelial cells after ovalbumin (OVA) inhalation. White bars, male mice; black bars, female mice; * p < 0.05 vs. male mice; # p < 0.05 vs. before OVA inhalation (Pre); ## p < 0.01 vs. before OVA inhalation (Pre). Data are shown as the mean ± standard error of the mean of three mice. (B) GM-CSF and CCL2 production from a human epithelial cell line, BEAS-2B, after the stimulation with TNF-α in the presence or absence of 17β-estradiol for 2 d. * p < 0.05. Data are presented as the mean ± standard deviation (SD) of triplicate cultures. (C) The proportion of CD86⁺ CD1c⁺ cells among CD14⁺ cells after incubation with supernatants collected in experiment B. * p < 0.05. Data are presented as the mean ± SD of triplicate cultures. (D) The expression levels of Cd86 mRNA in the cultured CD11c⁺ cells with BAL fluids prepared 2 d after OVA or saline inhalation. Data are presented as the mean ± SD of triplicate cultures. M, male mice; F, female mice; ** p < 0.01; NS, not significant. OVA, ovalbumin; Hrpt, hypoxanthine-guanine phosphoribosyltransferase; TNF-α, tumor necrosis factor-alpha; CCL2, chemokine (C-C motif) ligand 2; DC, dendritic cell; BAL, bronchoalveolar lavage; PBS, phosphate-buffered saline; IL33, interleukin 33; CD86, cluster of differentiation 86; RT-PCR, real-time reverse transcription-polymerase chain reaction; GM-CSF, granulocyte-macrophage colony-stimulating factor.

Figure 2

Schematic diagram illustrating the role of sex in the exacerbation of allergic asthma. Sex is associated with worse clinical outcomes of allergic asthma, including relatively higher prevalence, hospitalization rate, and relapse rate. This association is partly mediated by sex hormone-related alteration of innate and adaptive immune cells. Furthermore, in the immunological cascade from sensing allergens to airway cells, including epithelial cells and dendritic cells, to effector cell accumulation in surrounding airways, their responses are amplified based on sex. Meanwhile, the association of sex with other environmental factors such as psychological stress, respiratory infection, and upper airway inflammation induces sex-related dysmorphism of immune responses in asthma. In addition, the interplay between sex and genetic factors such as TSLP SNP rs2289276 or rs1837253 may also contribute to female-specific asthmatic immune responses. Thus, sex plays a multifaced role in female-dominant asthma pathogenesis. TSLP, thymic stromal lymphopoietin; SNP, single nucleotide polymorphism; RS, respiratory syncytial virus.