Sex Plays a Multifaceted Role in Asthma Pathogenesis

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

The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma

Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2)-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17)-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the μ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg) cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a “neuropsychiatry phenotype” in asthma

The involvement of central nervous system histamine receptors in psychological stress-induced exacerbation of allergic airway inflammation in mice

Background: Psychological stress is one of the major risk factors for asthma exacerbation. Although histamine in the brain acts as an excitatory and inhibitory neurotransmitter associated with psychological stress, the contribution of brain histamine to psychological stress-induced exacerbation of asthma remains unclear. The objective of this study was to investigate the role of histamine receptors in the CNS on stress induced asthma aggravation. Methods: We monitored the numbers of inflammatory cells and interleukin (IL)-13 levels in bronchoalveolar lavage fluid, airway responsiveness to inhaled methacholine, mucus secretion in airway epithelial cells, and antigen-specific IgE contents in sera in a murine model of stress-induced asthma treated with epinastine (an H1R antagonist), thioperamide (an H3/4R antagonist), or solvent. Results: All indicators of stress-induced asthma exacerbation were significantly reduced in stressed mice treated with epinastine compared with those treated with solvent, whereas treatment with thioperamide did not reduce the numbers of inflammatory cells in the stressed mice. Conclusions: These results suggest that H1R, but not H3/4R, may be involved in stress-induced asthma exacerbations in the central nervous system

CD8⁺ T Cells Mediate Female-Dominant IL-4 Production and Airway Inflammation in Allergic Asthma

<div><p>The prevalence and severity of bronchial asthma are higher in females than in males after puberty. Although antigen-specific CD8⁺ T cells play an important role in the development of asthma through their suppressive effect on cytokine production, the contribution of CD8⁺ T cells to sex differences in asthmatic responses remains unclear. In the present study, we investigated the sex-specific effect of CD8⁺ T cells in the suppression of asthma using an ovalbumin mouse model of asthma. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, lung type 2 T-helper cytokine levels, and interleukin-4 (IL-4) production by bronchial lymph node cells were significantly higher in female wild-type (WT) mice compared with male mice, whereas no such sex differences were observed between male and female <i>cd8α</i>-disrupted mice. The adaptive transfer of male, but not female, CD8⁺ T cells reduced the number of inflammatory cells in the recovered BAL fluid of male recipient mice, while no such sex difference in the suppressive activity of CD8⁺ T cells was observed in female recipient mice. Male CD8⁺ T cells produced higher levels of IFN-γ than female CD8⁺ T cells did, and this trend was associated with reduced IL-4 production by male, but not female, CD4⁺ T cells. Interestingly, IFN-γ receptor expression on CD4⁺ T cells was significantly lower in female mice than in male mice. These results suggest that female-dominant asthmatic responses are orchestrated by the reduced production of IFN-γ by CD8⁺ T cells and the lower expression of IFN-γ receptor on CD4⁺ T cells in females compared with males.</p></div

IFN-γ attenuates IL-4 production from BLN male CD4⁺ T cells.

<p>Male or female CD4⁺ T cells (2 x 10⁵ cells/well) and CD11c⁺ cells (2 x 10⁵ cells/well) were cultured with 50 μg/ml of OVA in presence of rIFN-γ (10 ng/ml) or vehicle for 72 h. Data are shown as the mean ± SD of triplicate cultures. Experiments were repeated twice with similar results. Open bars, male CD4⁺ T cells; closed bars, female CD4⁺ T cells. **, P < 0.01; NS, not significant.</p

Involvement of IFN-γ in sex differences in the inhibitory effect of BLN CD8⁺ T cells.

<p>(A) Intracellular cytokine expression by CD8⁺ T cells was analyzed using a flow cytometer. Data are shown as the mean ± SD of four mice. The expression of <i>Ifng</i> (B), <i>Gata3</i> and <i>Tbet</i> (C) in CD8⁺ T cells were measured by quantitative real-time RT-PCR. Data are shown as the mean ± SEM of four to eight mice. (D) Male CD4⁺ T cells (2 x 10⁵ cells/well), CD11c⁺ cells (2 x 10⁵ cells/well) and CD8⁺ T cells (0.66 x 10⁵ cells/well) were cultured with 50 μg/ml of OVA in presence of an anti- IFN-γ mAb (10 μg/ml) or control IgG for 72 h. The concentration of IL-4 in the culture supernatants was measured by ELISA. Data are shown as the mean ± SD of triplicate cultures. Experiment were repeated twice with similar results. *, P < 0.05; NS, not significant.</p

Sex differences in the inhibitory effect of BLN CD8⁺ T cells.

<p>Male (A) or female (B) CD4⁺ T cells (2 x 10⁵ cells/well) were cultured with CD8⁺ T cells (2 x 10⁵ cells/well) and splenic CD11c⁺ cells (2 x 10⁵ cells/well) in the presence of OVA (50 μg/ml) for 72 h. Concentration of IL-4 in the culture supernatants was measured by ELISA. Data are shown as the mean ± SD of triplicate cultures. Experiment were repeated twice with similar results. (C and D) Sensitized male or female CD8KO mice were adoptively transferred with CD8⁺ T cells from BLN of sensitized and challenged male (C) or female (D) WT mice. Saline was used as control of the transfer. Three days later, recipient CD8KO mice were challenged with OVA aerosol, and then sacrificed on day 5 post-OVA challenge. The numbers of inflammatory cells in BAL fluids were counted. Data are shown as the mean ± SEM from two independent experiments (n = 4–9). Open bars, male mice transferred with saline; closed bars, female mice transferred with saline; hatched bars, male mice transferred with male CD8⁺ T cells; horizontal line bars, female mice transferred with male CD8⁺ T cells; dotted bars, male mice transferred with female CD8⁺ T cells; vertical line bars, female mice transferred with female CD8⁺ T cells. −, mice transferred with saline; +, mice transferred with CD8⁺ T cells; *, P < 0.05; **, P < 0.01; NS, not significant.</p

Sex differences in inflammatory cell infiltration in BAL fluid.

<p>Male and female WT mice (A) and CD8KO mice (B) were sensitized and challenged. The number of inflammatory cells in BAL fluids were counted on day 5 after OVA challenge. Data are shown as the mean ± SEM from at least three independent experiments (n = 12–16). (C and D) The number of CD4⁺ and CD8⁺ T cells in BAL fluids of WT mice (C) and CD8KO mice (D) on day 5 after OVA challenge is shown. Each column represents the mean ± SEM of four to five mice. Open bars, male mice; closed bars, female mice.*, P < 0.05; NS, not significant.</p