丁酸盐对2型先天性淋巴细胞依赖性气道高反应性的调节
2018/06/04
摘要
背景：过敏性哮喘的特征是气道高反应性（AHR）和由异常TH2反应驱动的炎症。 2型先天性淋巴细胞（ILC2）是TH2细胞因子IL-5和IL-13的关键来源，而后者可以促进哮喘急性加重的发生。已有研究表明短链脂肪酸（SCFAs）可以减轻T细胞介导的变应性气道炎症。然而，它们在调控ILC2驱动的AHR和肺部炎症中的作用仍不清楚。
目的：我们对SCFAs在调控ILC2诱导的AHR和气道炎症中的免疫调节作用进行研究，并阐述了所涉及的机制。
方法：我们评估了SCFAs在调节肺来源的ILC2s的存活、增殖和细胞因子的产生中的作用。通过饮水或经鼻滴注的方式给予BALB/c小鼠SCFA丁酸盐，用以评估其在ILC2诱导的炎症反应中的作用即对IL-33和链格孢菌模型中的变应性炎症的反应。我们进一步应用人源ILC2s证实我们的发现。
结果：我们的研究显示，丁酸盐而非乙酸盐或丙酸盐抑制了小鼠ILC2s产生IL-13和IL-5。全身和局部应用丁酸盐可显着改善ILC2诱导的AHR和气道炎症。我们进一步证明丁酸盐抑制ILC2的增殖和GATA3的表达，但并不诱导细胞凋亡。且这一作用可能是通过抑制组蛋白去乙酰化酶（HDAC）而产生的，类似于TSA（pan-HDAC抑制剂）的作用。重要的是，联合应用TSA和丁酸盐并未导致累加效应。最后，我们的研究显示丁酸盐可以减少人源ILC2中的细胞因子的产生。
结论：我们的研究结果证实丁酸盐对HDAC的抑制作用是ILC2的增殖和功能的关键调节因子，并可能成为哮喘的潜在治疗靶点。
Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by butyrate
Abstract
BACKGROUND：Allergic asthma is characterized airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 response. Type 2 innate lymphoid cells (ILC2s) are a critical source of TH2 cytokines IL-5 and IL-13 which promote acute asthma exacerbation. Short chain fatty acids (SCFAs) have been shown to attenuate T cell- mediated allergic airway inflammation. Their role in the regulation of ILC2-driven AHR and lung inflammation, however, remains unknown.
OBJECTICE：We investigated the immunomodulatory role of SCFAs in the regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
METHODS：We assessed the role of SCFAs in regulating the survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.
RESULTS：We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition as TSA, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, co-treatment of TSA and butyrate did not result in additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
CONCLUSIONS：Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity, and may serve as a potential therapeutic target for asthma.
背景：过敏性哮喘的特征是气道高反应性（AHR）和由异常TH2反应驱动的炎症。 2型先天性淋巴细胞（ILC2）是TH2细胞因子IL-5和IL-13的关键来源，而后者可以促进哮喘急性加重的发生。已有研究表明短链脂肪酸（SCFAs）可以减轻T细胞介导的变应性气道炎症。然而，它们在调控ILC2驱动的AHR和肺部炎症中的作用仍不清楚。
目的：我们对SCFAs在调控ILC2诱导的AHR和气道炎症中的免疫调节作用进行研究，并阐述了所涉及的机制。
方法：我们评估了SCFAs在调节肺来源的ILC2s的存活、增殖和细胞因子的产生中的作用。通过饮水或经鼻滴注的方式给予BALB/c小鼠SCFA丁酸盐，用以评估其在ILC2诱导的炎症反应中的作用即对IL-33和链格孢菌模型中的变应性炎症的反应。我们进一步应用人源ILC2s证实我们的发现。
结果：我们的研究显示，丁酸盐而非乙酸盐或丙酸盐抑制了小鼠ILC2s产生IL-13和IL-5。全身和局部应用丁酸盐可显着改善ILC2诱导的AHR和气道炎症。我们进一步证明丁酸盐抑制ILC2的增殖和GATA3的表达，但并不诱导细胞凋亡。且这一作用可能是通过抑制组蛋白去乙酰化酶（HDAC）而产生的，类似于TSA（pan-HDAC抑制剂）的作用。重要的是，联合应用TSA和丁酸盐并未导致累加效应。最后，我们的研究显示丁酸盐可以减少人源ILC2中的细胞因子的产生。
结论：我们的研究结果证实丁酸盐对HDAC的抑制作用是ILC2的增殖和功能的关键调节因子，并可能成为哮喘的潜在治疗靶点。
(中国医科大学附属第一医院呼吸与危重症医学科 李文扬 摘译 杨冬 审校)
(Christina Li-Ping Thio MSa,et al. JACI 2018 Mar 3 Abstract )
(Christina Li-Ping Thio MSa,et al. JACI 2018 Mar 3 Abstract )
Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by butyrate
Abstract
BACKGROUND：Allergic asthma is characterized airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 response. Type 2 innate lymphoid cells (ILC2s) are a critical source of TH2 cytokines IL-5 and IL-13 which promote acute asthma exacerbation. Short chain fatty acids (SCFAs) have been shown to attenuate T cell- mediated allergic airway inflammation. Their role in the regulation of ILC2-driven AHR and lung inflammation, however, remains unknown.
OBJECTICE：We investigated the immunomodulatory role of SCFAs in the regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
METHODS：We assessed the role of SCFAs in regulating the survival, proliferation, and cytokine production in lung sorted ILC2s. The SCFA butyrate was administered through drinking water or intranasally in BALB/c mice to evaluate its role in ILC2-driven inflammatory response in IL-33 and Alternaria alternata models of allergic inflammation. We further confirmed our findings in human ILC2s.
RESULTS：We show that butyrate, but not acetate or propionate, inhibited IL-13 and IL-5 production by murine ILC2s. Systemic and local administration of butyrate significantly ameliorated ILC2-driven AHR and airway inflammation. We further demonstrate that butyrate inhibited ILC2 proliferation and GATA3 expression but did not induce cell apoptosis, likely through histone deacetylase (HDAC) inhibition as TSA, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, co-treatment of TSA and butyrate did not result in additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
CONCLUSIONS：Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity, and may serve as a potential therapeutic target for asthma.
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重症哮喘生物制剂及热成形术时代的不依从性
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