Androgen Plays a Potential Novel Hormonal Therapeutic Role in Th17 Cells Predominant Neutrophilic Severe Asthma by Attenuating BECs Regulated Th17 Cells Differentiation via MBD2 Expression

Abstract

T helper 17 (Th17) cells subtype of non-T2 asthma is less responsive (resistant) to inhaled corticosteroids (ICS), so also called severe asthma. Methyl-CpG-binding domain protein 2 (MBD2) regulates the differentiation of the Th17 cells, showing the possibility of a therapeutic target in severe asthma. Androgen tends to show beneficial therapeutic effects and is a “hot research topic,” but its role in the differentiation and expression of Th17 cells via MBD2 is still unknown. The aim of this study was to evaluate how sex hormone interacts with MBD2 and affects the differentiation and expression of Th17 cells in severe asthma. Here, first, we measured the concentration of androgen, estrogen, and androgen estrogen ratio from subjects and correlated it with severe asthma status. Then, we established an animal model and bronchial epithelial cells (BECs) model of severe asthma to evaluate the role of MBD2 in the differentiation and expression of Th17 cells (IL-17), the therapeutic potential of sex hormones in severe asthma, and the effect of sex hormones in BECs regulated Th17 cells differentiation via MBD2 at the cellular level. Increased MBD2 expression and Th17 cells differentiation were noted in the animal and the BECs severe asthma models. Th17 cell differentiation and expression were MBD2 dependent. Androgen attenuated the differentiation of BECs regulated Th17 cells via MBD2 showing BECs as a therapeutic target of androgen, and these findings postulate the novel role of androgen in Th17 cells predominant neutrophilic severe asthma therapy through targeting MBD2.

Combination of androgen and estrogen improves asthma by mediating Runx3 expression

“…We have found disturbed sex hormone balances among asthma patients both in men and women, we next tend to explore whether hormone intervention could influence asthmatic pathophysiological changes. We established murine models for asthma according to previous studies 13 - 15 . Similar to the findings observed in human participants, we have found that the serum DHT concentrations decreased significantly in mice with experimental asthma, while the E2 concentrations elevated comparing to control mice (Figure 2 A-C).…”

“…Androgens, on the other hand, are reported to exert anti-asthma effects. Low levels of endogenous anabolic androgens are associated with poorer asthma control in female patients 40 , and androgens could alleviate both Th2 and Th17 mediated airway inflammations seen in asthma 41 , 42 , implicating its potential therapeutic application. In the present study we have found that combination of estrogen (E2) and androgen (DHT) have better effects on mitigating airway inflammations in asthma than single use of either hormone.…”

“…A murine asthma model was established in accordance with our previous reports [14,15]. In brief, mice mere intraperitoneally (i.e.)…”

“…In our previous studies, we have found that bronchial epithelial cells (BECs) could contribute to the pathogenesis of asthma via affecting the differentiation of T helper cells [13][14][15]28], we next sought to determine whether sex hormones intervention influence Th1/Th2 balance and the possible underlying mechanisms. DHT, E2, or combination of DHT and E2 were applied to intervene primary murine BECs and CD4+ naïve T cell co-culture systems [32] (Figure 5A).…”

“…The naive CD4 + T cells differentiate into Th1 cells or Th2 cells with the immune stimuli provided by antigen-presenting cells (APCs). Our recent researches have suggested that bronchial epithelial cells (BECs) could act as non-canonical APCs and modulate the differentiation of naïve T cells [13][14][15], and it had been reported that sex hormones could modulate innate and adaptive immune responses through regulation of dendritic cells (DCs) and resident macrophages [4,16], yet it is unknown whether sex hormones could influence airway inflammation via BECs.…”