TGF-β1在流感病毒引起的睾丸免疫反应中的调节作用
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摘要
睾丸是一种具有免疫豁免特权的器官,睾丸中的免疫细胞(如巨噬细胞,T细胞,树突状细胞等)与睾丸间质细胞(LC细胞)紧密相邻,都位于间质区域,暗示它们之间存在着功能间的相互作用。LC细胞除了产生雄激素,也产生许多细胞因子,如TGF-β1, IL-6, IL-1α。这些细胞因子能够直接影响与其相邻的免疫细胞。尽管睾丸是具有免疫豁免的器官,它仍然能被许多病原体感染,而且许多男性生殖道感染是无症状或未被确诊的。甲型流感病毒(IAV)是季节性流感及流感大流行的病原体,它所造成的的某些原因不明的严重症状表明,流感病毒可能在人类中引起更为复杂的疾病。流感病毒已经被假设能够引起睾丸炎,但早期的病例报道时间非常久远,并且当时的技术水平还没有从睾丸中分离出流感病毒,因此没有直接证据支持这一假说。
本研究使用甲型流感病毒感染小鼠和雪貂作为动物模型,研究其所引起的睾丸炎及其恢复机理。结果表明甲型流感病毒(WSN,2009H1N1,2009H5N1, H3N2和H7N9)通过直接感染小鼠及雪貂的LC细胞引起一过性睾丸炎。流感病毒受体SA-a2,3-半乳糖-和SA-a2,6-半乳糖-唾液酸主要定位于睾丸LC表面,但是两种流感病毒受体在睾丸间质细胞干细胞(SLC)中都不表达,因此流感病毒侵入睾丸后,LC细胞被感染破坏,SLC则不会受到感染,由于LC细胞是睾丸TGF-β1的主要来源,它受到破坏引起TGF-β1表达量降低,低水平的TGF-β1引起SLC启动自我更新及分化,补充受到破坏的LC细胞,新生无病毒的LC细胞,使血清睾酮水平恢复到正常范围,同时TGF-β1表达量恢复到正常水平,从而引起调节性T细胞(Treg)数量的上升,并最终使睾丸恢复到正常状态。二氢睾酮预处理使小鼠组织中Treg水平升高,能够削弱机体过激的免疫反应,减轻小鼠的发病率和死亡率,并能够阻止睾丸炎的发生。另外,106例流感时期病人(H3N2-,2009-H1N1-和2013-H7N9-病例)的血清学分析表明,睾酮水平在急性感染期显著下降,恢复期逐渐恢复到正常值,人睾丸穿刺切片也检测到流感病毒受体的表达,说明其具有广谱性。
本研究表明,TGF-β1在调控SLC的活化,Treg细胞的诱导,以及维持睾丸稳态和睾丸免疫豁免过程中发挥着极其重要的作用,另外,本研究提出将雄激素受体作为预防和治疗甲型流感病毒感染的潜在研究靶标。
The testis is an organ with immune privilege. Majority of the immune cells (e.g., macrophages, T cells and dendritic cells) and all Leydig cells (LCs) are located in the interstitial compartment, suggesting that there are functional interactions/communications between these cells. In addition to the production of testosterone (T), a body of evidence shows that LCs produce cytokines such as TGF-β1, IL-6and IL-1α. These factors must directly influence the immune cells. While it is an immune privileged organ, testis infection by viruses, bacteria or parasites has been reported, and many male reproductive tract infections are asymptomatic and undiagnosed. Influenza A virus (IAV) is the causative agent of both the seasonal flu and occasional pandemics. The certain unexplained severe pathologies caused by IAVs indicate that they can cause more complex and ill-defined diseases in humans. IAV infection has been hypothesized to cause orchitis, but the early case report supporting this hypothesis was from long before the influenza virus was isolated and characterized, and no direct evidence has been found to support this theory.
Our study using mice and ferrets infected with IAV as animal models to study the orchitis caused by IAV and the recovery mechanism. Herein, we demnonstrated that IAVs (WSN,2009H1N1,2009H5N1, H3N2, and H7N9) caused transient-orchitis by directly destroying LCs in different mouse strains and ferrets. IAV receptors:SA-α2,3-Gal-and SA-a2,6-Gal-linked sialic-acid were predominantly localized in LCs. However, due to the lack of IAV-receptors, the spindle-like stem LCs (SLCs) were free of viral-infection, then resumed self-renewal and differentiation upon TGF-β1decreasing due to the depletion of LCs. The resumed self-renewal resulted in viral-free LCs regeneration, followed quick recovery of serum T and simultaneous increased testicular regulatory T cells (Tregs) from the infected testes via TGF-(31signaling in an androgen/androgen receptor (AR)-dependent manner, which in turn led to orchitis recovery. Pretreated-dihydrotestosterone in mice resulted in increased testicular Tregs, prevented orchitis and reduced morbidity and mortality. Furthermore, T levels were decreased in acute-phase and recovered from106pandemic-flu patients (H3N2-,2009-H1N1-, and2013-H7N9-cases), IAV receptors were also detected in human testis. Data reveals the distinct roles of testicular TGF-β1in regulating SLC-activation and Treg induction, orchestrating testicular homeostasis and testicular immune-response, further raise AR as a potential-target for IAVs prevention.
本研究使用甲型流感病毒感染小鼠和雪貂作为动物模型,研究其所引起的睾丸炎及其恢复机理。结果表明甲型流感病毒(WSN,2009H1N1,2009H5N1, H3N2和H7N9)通过直接感染小鼠及雪貂的LC细胞引起一过性睾丸炎。流感病毒受体SA-a2,3-半乳糖-和SA-a2,6-半乳糖-唾液酸主要定位于睾丸LC表面,但是两种流感病毒受体在睾丸间质细胞干细胞(SLC)中都不表达,因此流感病毒侵入睾丸后,LC细胞被感染破坏,SLC则不会受到感染,由于LC细胞是睾丸TGF-β1的主要来源,它受到破坏引起TGF-β1表达量降低,低水平的TGF-β1引起SLC启动自我更新及分化,补充受到破坏的LC细胞,新生无病毒的LC细胞,使血清睾酮水平恢复到正常范围,同时TGF-β1表达量恢复到正常水平,从而引起调节性T细胞(Treg)数量的上升,并最终使睾丸恢复到正常状态。二氢睾酮预处理使小鼠组织中Treg水平升高,能够削弱机体过激的免疫反应,减轻小鼠的发病率和死亡率,并能够阻止睾丸炎的发生。另外,106例流感时期病人(H3N2-,2009-H1N1-和2013-H7N9-病例)的血清学分析表明,睾酮水平在急性感染期显著下降,恢复期逐渐恢复到正常值,人睾丸穿刺切片也检测到流感病毒受体的表达,说明其具有广谱性。
本研究表明,TGF-β1在调控SLC的活化,Treg细胞的诱导,以及维持睾丸稳态和睾丸免疫豁免过程中发挥着极其重要的作用,另外,本研究提出将雄激素受体作为预防和治疗甲型流感病毒感染的潜在研究靶标。
The testis is an organ with immune privilege. Majority of the immune cells (e.g., macrophages, T cells and dendritic cells) and all Leydig cells (LCs) are located in the interstitial compartment, suggesting that there are functional interactions/communications between these cells. In addition to the production of testosterone (T), a body of evidence shows that LCs produce cytokines such as TGF-β1, IL-6and IL-1α. These factors must directly influence the immune cells. While it is an immune privileged organ, testis infection by viruses, bacteria or parasites has been reported, and many male reproductive tract infections are asymptomatic and undiagnosed. Influenza A virus (IAV) is the causative agent of both the seasonal flu and occasional pandemics. The certain unexplained severe pathologies caused by IAVs indicate that they can cause more complex and ill-defined diseases in humans. IAV infection has been hypothesized to cause orchitis, but the early case report supporting this hypothesis was from long before the influenza virus was isolated and characterized, and no direct evidence has been found to support this theory.
Our study using mice and ferrets infected with IAV as animal models to study the orchitis caused by IAV and the recovery mechanism. Herein, we demnonstrated that IAVs (WSN,2009H1N1,2009H5N1, H3N2, and H7N9) caused transient-orchitis by directly destroying LCs in different mouse strains and ferrets. IAV receptors:SA-α2,3-Gal-and SA-a2,6-Gal-linked sialic-acid were predominantly localized in LCs. However, due to the lack of IAV-receptors, the spindle-like stem LCs (SLCs) were free of viral-infection, then resumed self-renewal and differentiation upon TGF-β1decreasing due to the depletion of LCs. The resumed self-renewal resulted in viral-free LCs regeneration, followed quick recovery of serum T and simultaneous increased testicular regulatory T cells (Tregs) from the infected testes via TGF-(31signaling in an androgen/androgen receptor (AR)-dependent manner, which in turn led to orchitis recovery. Pretreated-dihydrotestosterone in mice resulted in increased testicular Tregs, prevented orchitis and reduced morbidity and mortality. Furthermore, T levels were decreased in acute-phase and recovered from106pandemic-flu patients (H3N2-,2009-H1N1-, and2013-H7N9-cases), IAV receptors were also detected in human testis. Data reveals the distinct roles of testicular TGF-β1in regulating SLC-activation and Treg induction, orchestrating testicular homeostasis and testicular immune-response, further raise AR as a potential-target for IAVs prevention.
引文
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