μ-opioid Receptor-Mediated Alterations of Allergen-Induced Immune Responses of Bronchial Lymph Node Cells in a Murine Model of Stress Asthma

ABSTRACTBackgroundPsychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear.MethodsMOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured.ResultsStress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes.ConclusionsRestraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs

アレルギー性気道炎症の性差の加齢変化-サイトカイン産生とプロゲステロンの影響に関する検討-

The incidence,severity and prognosis of asthma can be affected by a number of factors,including the patient\u27s age and sex.Clinical observations and epidemiologic studies indicate that the severity of asthma is higher among boys than girls,but that the ratio inverts after puberty.Thereafter,in the elderly,the sex difference disappears.However,the mechanisms underlying the age-related sex differences in the severity of asthma are not clear.Therefore,to clarify the mechanisms we compared using a murine model of asthma allergen-induced airway inflammation and the effect of progesterone on antigen-induced cytokine production by lymphocytes betoween the different age and sex.In 6 weeks old C57BL/6 mice,the airway inflammation in flammation in female mice sensitized with OVA followed by OVA inhalation was more severe than in male mice,whereas the sex difference in the airway inflammation was not observed in 16 weeks old mice.In not only 6 but also 16 weeks old mice,bronchial lymph nodes (BLN) cells from OVA-sensitized female mice produced more Th2 cytokine,than those from age-matched male mice,upon simulation with OVA.Progesterone did not significantly affect the sex difference in Th2 cytokine production by BLN cells in either 6 or 16 weeks old mice.Our findings suggest that the age-related sex differences in allergic airway inflammation are not due to simply the differences in lymphocytes function and sensiticities to progesterone

アレルギー性気道炎症における性ホルモンおよびリンパ球の役割

Epidemiological data indicate that the prevalence and severity of asthma is higher among females than males after puberty. The influence of sex on asthma incidence suggests that sex hormones could play a role in the pathogenesis of the condition associated with asthma. However, the mechanisms of the affect of sex are not clear. Therefore, in the current study, we investigated the sex differences in allergic inflammation in terms of lymphocyte function, using a murine model of allergic asthma. In either BALB/c or C57BL/6J mice, the airway inflammation in female mice sensitized with OVA followed by OVA inhalation was more severe than that in male mice. The contents of Th2 cytokines, such as IL-4, IL-5 and IL-13, in bronchoalveolar lavage fluid from female mice were significantly increased compared with male mice. The airway inflammation in female mice after adoptive transfer of splenocyte from sensitized female mice was more severe than that in any other combination of donors and recipients. Furthermore, splenocytes from sensitized female mice produced more Th2 cytokines than those from sensitized male mice, upon stimulation with OVA. The degree of airway inflammation induced by lipopolysaccharide inhalation was not significantly different between male and female mice. Our findings suggest that sex differences in allergic airway inflammation are due to those in not only sex hormones but also lymphocytes function

中枢性μ-オピオイド受容体とグルココルチコイド受容体を介した慢性ストレスによる喘息悪化

Stress and other psychological factors have long been etiologically demonstrated to be associated with asthma symptoms. We recently reported that μ-opioid receptors (MORs) were involved in asthma exacerbations caused by psychological stress in a murine asthma model. On the other hand, MOR activation in central nervous system (CNS) by psychological stress can stimulate hypothalamus-pituitary-adrenal (HPA) axis, resulting in the release of glucocorticoid. Glucocorticoid has been reported to shift the immune response from helper T (Th) 1 to Th2. These findings led us to hypothesize that psychological stress-induced exacerbations of asthma was attributable to cortisol release due to HPA axis stimulation via the activation of MOR in CNS. Female C57BL/6 mice sensitized with ovalbumin were exposed to chronic restraint stress as psychological stress. Either intracereberoventricular administration of an MOR antagonist or systemic administration of a glucocorticoid receptor antagonist during stress exposure abolished stress-induced exacerbation of airway inflammation. On the other hand, the elevation of stress-induced plasma corticosterone level was not affected by the administration of the MOR antagonist to CNS, and observed also in MOR knockout mice. These results suggest that both MOR in CNS and glucocorticoid are involved in the psychological stress-induced exacerbation of allergic airway inflammation, but the sress-induced HPA axis stimulation did not depend on MOR activation in this model

抗原誘発性Th1・Th2サイトカイン産生に対する性ホルモンの影響の性差

The incidence, severity and prognosis of asthma can be affected by a number of factors, including the patient\u27s age and sex. Clinical observations and epidemiologic studies indicate that the prevalence and severity of asthma is higher among boys than girls, but that the ratio inverts after puberty. The reversal of the male/female prevalence of asthma at puberty strongly suggests a role of sex hormones. However, the mechanisms underlying the gender differences in the prevalence of asthma are not clear. Recently, we suggested that the sex differences were due to those in not only sex hormones but also lymphocyte functions based on findings in a murine model of allergic asthma. Therefore, we investigated the effect of sex hormones on antigen-induced cytokine production by lymphocytes to further investigate these gender differences. Splenocytes from ovalbumin (OVA)-sensitized female mice produced more IL-5, Th2 cytokine, than those from OVA-sensitized male mice, upon simulation with OVA. Progesterone decreased the production of IFN-g, Th1 cytokine, by splenocytes from both sensitized male and female mice. 17β-estradiol had no effect on Th1 and Th2 cytokine production by splenocytes from both mice. However, 5a-dihydrotestosterone decreased the production of Th2 cytokines by splenoytes from sensitized female mice but not these from male mice. Our findings suggest that lymphocytes from males and females have different sensitivities to sex hormones in antigen-induced cytokine production

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