丁酸调控2型固有淋巴细胞依赖的气道高反应性
2018/06/20
摘要
背景：过敏性哮喘以TH2反应驱动的气道高反应性（AHR）和炎症为特征。2型固有淋巴细胞（ILC2s）是TH2细胞因子IL-5和IL-13的关键来源，这些细胞因子可以促进哮喘急性发作。短链脂肪酸（Short-chain fatty acids，SCFAs）已经被证实可以减轻T细胞介导的过敏性气道炎症。但是它们在调控ILC2介导的AHR和肺部炎症中的作用仍然不得而知。
目的：我们探索SCFAs在调控ILC2诱导的AHR和气道炎症中的免疫调节作用并阐释其机制。
方法学：我们评估了SCFAs在调节肺分选的ILC2s的存活、增殖和细胞因子产生中的作用。BALB/c小鼠通过饮水或鼻饲的方式注入SCFA丁酸，从而评估其在IL-33和链格孢过敏性炎症模型中对ILC驱动免疫反应的作用。我们进一步在人ILC2s中证实了我们的发现。
结果：我们发现丁酸，而不是乙酸和丙酸，抑制了小鼠ILC2s的IL-13和IL-5的产生。全身和局部给予丁酸显著地减轻ILC2介导的AHR与气道炎症。我们进一步证明丁酸抑制了ILC2增殖和GATA3表达，但是并未诱导细胞凋亡，（其潜在机制）可能是通过抑制组蛋白去乙酰化酶（histone deacetylase，HDAC），因为TSA（1个非特异性的HDAC抑制剂，）对ILC2s显示了相似的作用。最后，我们证实丁酸降低人ILC2细胞因子的产生。
结论：我们的结果发现丁酸通过其HDAC抑制活性，是ILC2增殖与功能关键调节剂，它可能作为哮喘潜在的治疗靶点。
Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by
Butyrate
Thio CL, Chi PY, Lai AC, Chang YJ.
J Allergy Clin Immunol. 2018 Mar 6. pii: S0091-6749(18)30325-7
Abstract
BACKGROUND: Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the 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. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.
OBJECTIVE: We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
METHODS: We assessed the role of SCFAs in regulating 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 the 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, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
CONCLUSION: Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma.
背景：过敏性哮喘以TH2反应驱动的气道高反应性（AHR）和炎症为特征。2型固有淋巴细胞（ILC2s）是TH2细胞因子IL-5和IL-13的关键来源，这些细胞因子可以促进哮喘急性发作。短链脂肪酸（Short-chain fatty acids，SCFAs）已经被证实可以减轻T细胞介导的过敏性气道炎症。但是它们在调控ILC2介导的AHR和肺部炎症中的作用仍然不得而知。
目的：我们探索SCFAs在调控ILC2诱导的AHR和气道炎症中的免疫调节作用并阐释其机制。
方法学：我们评估了SCFAs在调节肺分选的ILC2s的存活、增殖和细胞因子产生中的作用。BALB/c小鼠通过饮水或鼻饲的方式注入SCFA丁酸，从而评估其在IL-33和链格孢过敏性炎症模型中对ILC驱动免疫反应的作用。我们进一步在人ILC2s中证实了我们的发现。
结果：我们发现丁酸，而不是乙酸和丙酸，抑制了小鼠ILC2s的IL-13和IL-5的产生。全身和局部给予丁酸显著地减轻ILC2介导的AHR与气道炎症。我们进一步证明丁酸抑制了ILC2增殖和GATA3表达，但是并未诱导细胞凋亡，（其潜在机制）可能是通过抑制组蛋白去乙酰化酶（histone deacetylase，HDAC），因为TSA（1个非特异性的HDAC抑制剂，）对ILC2s显示了相似的作用。最后，我们证实丁酸降低人ILC2细胞因子的产生。
结论：我们的结果发现丁酸通过其HDAC抑制活性，是ILC2增殖与功能关键调节剂，它可能作为哮喘潜在的治疗靶点。
（刘影 王刚 四川大学华西医院中西医结合科呼吸组）
（J Allergy Clin Immunol. 2018 Mar 6. pii: S0091-6749(18)30325-7）
（J Allergy Clin Immunol. 2018 Mar 6. pii: S0091-6749(18)30325-7）
Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by
Butyrate
Thio CL, Chi PY, Lai AC, Chang YJ.
J Allergy Clin Immunol. 2018 Mar 6. pii: S0091-6749(18)30325-7
Abstract
BACKGROUND: Allergic asthma is characterized by airway hyperreactivity (AHR) and inflammation driven by aberrant TH2 responses. Type 2 innate lymphoid cells (ILC2s) are a critical source of the 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. However, their role in regulation of ILC2-driven AHR and lung inflammation remains unknown.
OBJECTIVE: We investigated the immunomodulatory role of SCFAs in regulation of ILC2-induced AHR and airway inflammation and delineated the mechanism involved.
METHODS: We assessed the role of SCFAs in regulating 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 the 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, because trichostatin A, a pan-HDAC inhibitor, exerted similar effects on ILC2s. Importantly, cotreatment with trichostatin A and butyrate did not result in an additive effect. Finally, we show that butyrate reduces cytokine production in human ILC2s.
CONCLUSION: Our findings identify butyrate as a critical regulator of ILC2 proliferation and function through its HDAC inhibitory activity and can serve as a potential therapeutic target for asthma.
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哮喘控制，肺功能，营养状况和与健康相关的生活质量：成年男性和女性哮喘之间的差异
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与年龄相关的鼻炎-鼻窦炎及鼻息肉与哮喘发作的关系
