TSLP和IL-33相互促进肺蛋白表达和ILC2受体表达增强先天2型气道炎症
2020/10/14
摘要
背景：上皮细胞衍生的危险信号介质胸腺基质淋巴细胞生成素(TSLP)和白细胞介素-33(IL-33)一直与哮喘的适应性Th2免疫反应有关。此外，TSLP和IL-33协同促进2型先天性淋巴细胞(ILC2)活化，诱导先天性过敏性炎症。然而，这种协同激活ILC2的机制尚不清楚。
方法：BALB/c 野生型和TSLP受体缺陷型 (TSLPR-/- ) 小鼠连续4天给予链格孢提取物（Alt-Ext）或PBS进行鼻内激发，以评估先天性气道过敏性炎症。预先给予rTSLP或溶媒的野生型小鼠、TSLPR-/-小鼠和IL-33受体缺陷型（ST2-/-）小鼠鼻内给予Alt-Ext或溶媒激发一次或两次，以评估IL-33的释放和肺组织中TSLP的表达。采用流式细胞术检测rTSLP、rIL-33、rTSLP+rIL-33或溶媒处理后的肺ILC2上TSLPR和ST2的表达。
结果：与野生型小鼠相比，胸腺基质淋巴细胞生成素受体缺陷型小鼠在Alt-Ext激发后，表达IL-5和IL-13的肺ILC2数量显著减少。另外，与野生型小鼠相比，TSLPR-/- 小鼠的嗜酸性粒细胞增多症、肺组织IL-4、IL-5和IL-13蛋白水平以及气道黏液评分也显著降低。内源性和外源性TSLP增加了Alt-Ext诱导的IL-33向BALF的释放，而ST2缺乏降低了Alt-Ext诱导的TSLP在肺组织中的表达。此外，rTSLP和rIL-33治疗在体内和体外均能相互促进彼此肺ILC2受体的表达。
结论：胸腺基质淋巴细胞生成素和IL-33信号在Alt-Ext激发后相互促进彼此蛋白在肺组织中的释放和表达，并且促进彼此受体在肺ILC2上的表达，从而增强ILC2的激活。
TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation.
Shinji Toki, Kasia Goleniewska, Jian Zhang, Weisong Zhou, Dawn C Newcomb, Baohua Zhou, Hirohito Kita, Kelli L Boyd, Ray S Peebles Jr.
Abstract
BACKGROUND:The epithelial cell-derived danger signal mediators thymic stromal lymphopoietin (TSLP) and IL-33 are consistently associated with adaptive Th2 immune responses in asthma. In addition, TSLP and IL-33 synergistically promoted group 2 innate lymphoid cell (ILC2) activation to induce innate allergic inflammation. However, the mechanism of this synergistic ILC2 activation is unknown.
METHODS:BALB/c WT and TSLP receptor-deficient (TSLPR-/- ) mice were challenged intranasally with Alternaria extract (Alt-Ext) or PBS for 4 consecutive days to evaluate innate airway allergic inflammation. WT mice pre-administered with rTSLP or vehicle, TSLPR-/- mice, and IL-33 receptor-deficient (ST2-/- ) mice were challenged intranasally with Alt-Ext or vehicle once or twice to evaluate IL-33 release and TSLP expression in the lung. TSLPR and ST2 expression on lung ILC2 were measured by flow cytometry after treatment of rTSLP, rIL-33, rTSLP + rIL-33, or vehicle.
RESULTS:Thymic stromal lymphopoietin receptor deficient mice had significantly decreased the number of lung ILC2 expressing IL-5 and IL-13 following Alt-Ext-challenge compared to WT mice. Further, eosinophilia, protein level of lung IL-4, IL-5, and IL-13, and airway mucus score were also significantly decreased in TSLPR-/- mice compared to WT mice. Endogenous and exogenous TSLP increased Alt-Ext-induced IL-33 release into BALF, and ST2 deficiency decreased Alt-Ext-induced TSLP expression in the lung. Further, rTSLP and rIL-33 treatment reciprocally increased each other's receptor expression on lung ILC2 in vivo and in vitro.
CONCLUSIONS:Thymic stromal lymphopoietin and IL-33 signaling reciprocally enhanced each other's protein release and expression in the lung following Alt-Ext-challenge and each other's receptor expression on lung ILC2 to enhance ILC2 activation.
背景：上皮细胞衍生的危险信号介质胸腺基质淋巴细胞生成素(TSLP)和白细胞介素-33(IL-33)一直与哮喘的适应性Th2免疫反应有关。此外，TSLP和IL-33协同促进2型先天性淋巴细胞(ILC2)活化，诱导先天性过敏性炎症。然而，这种协同激活ILC2的机制尚不清楚。
方法：BALB/c 野生型和TSLP受体缺陷型 (TSLPR-/- ) 小鼠连续4天给予链格孢提取物（Alt-Ext）或PBS进行鼻内激发，以评估先天性气道过敏性炎症。预先给予rTSLP或溶媒的野生型小鼠、TSLPR-/-小鼠和IL-33受体缺陷型（ST2-/-）小鼠鼻内给予Alt-Ext或溶媒激发一次或两次，以评估IL-33的释放和肺组织中TSLP的表达。采用流式细胞术检测rTSLP、rIL-33、rTSLP+rIL-33或溶媒处理后的肺ILC2上TSLPR和ST2的表达。
结果：与野生型小鼠相比，胸腺基质淋巴细胞生成素受体缺陷型小鼠在Alt-Ext激发后，表达IL-5和IL-13的肺ILC2数量显著减少。另外，与野生型小鼠相比，TSLPR-/- 小鼠的嗜酸性粒细胞增多症、肺组织IL-4、IL-5和IL-13蛋白水平以及气道黏液评分也显著降低。内源性和外源性TSLP增加了Alt-Ext诱导的IL-33向BALF的释放，而ST2缺乏降低了Alt-Ext诱导的TSLP在肺组织中的表达。此外，rTSLP和rIL-33治疗在体内和体外均能相互促进彼此肺ILC2受体的表达。
结论：胸腺基质淋巴细胞生成素和IL-33信号在Alt-Ext激发后相互促进彼此蛋白在肺组织中的释放和表达，并且促进彼此受体在肺ILC2上的表达，从而增强ILC2的激活。
(中日友好医院呼吸与危重症医学科 王静茹 摘译 林江涛 审校 )
(Allergy.2020, 75(7):1606-1617. doi: 10.1111/all.14196.)
(Allergy.2020, 75(7):1606-1617. doi: 10.1111/all.14196.)
TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation.
Shinji Toki, Kasia Goleniewska, Jian Zhang, Weisong Zhou, Dawn C Newcomb, Baohua Zhou, Hirohito Kita, Kelli L Boyd, Ray S Peebles Jr.
Abstract
BACKGROUND:The epithelial cell-derived danger signal mediators thymic stromal lymphopoietin (TSLP) and IL-33 are consistently associated with adaptive Th2 immune responses in asthma. In addition, TSLP and IL-33 synergistically promoted group 2 innate lymphoid cell (ILC2) activation to induce innate allergic inflammation. However, the mechanism of this synergistic ILC2 activation is unknown.
METHODS:BALB/c WT and TSLP receptor-deficient (TSLPR-/- ) mice were challenged intranasally with Alternaria extract (Alt-Ext) or PBS for 4 consecutive days to evaluate innate airway allergic inflammation. WT mice pre-administered with rTSLP or vehicle, TSLPR-/- mice, and IL-33 receptor-deficient (ST2-/- ) mice were challenged intranasally with Alt-Ext or vehicle once or twice to evaluate IL-33 release and TSLP expression in the lung. TSLPR and ST2 expression on lung ILC2 were measured by flow cytometry after treatment of rTSLP, rIL-33, rTSLP + rIL-33, or vehicle.
RESULTS:Thymic stromal lymphopoietin receptor deficient mice had significantly decreased the number of lung ILC2 expressing IL-5 and IL-13 following Alt-Ext-challenge compared to WT mice. Further, eosinophilia, protein level of lung IL-4, IL-5, and IL-13, and airway mucus score were also significantly decreased in TSLPR-/- mice compared to WT mice. Endogenous and exogenous TSLP increased Alt-Ext-induced IL-33 release into BALF, and ST2 deficiency decreased Alt-Ext-induced TSLP expression in the lung. Further, rTSLP and rIL-33 treatment reciprocally increased each other's receptor expression on lung ILC2 in vivo and in vitro.
CONCLUSIONS:Thymic stromal lymphopoietin and IL-33 signaling reciprocally enhanced each other's protein release and expression in the lung following Alt-Ext-challenge and each other's receptor expression on lung ILC2 to enhance ILC2 activation.
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环状RNA circHIPK3通过miR-326/STIMI轴调节气道平滑肌细胞的增值
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