室内尘螨驱动了促炎的花生四烯酸重组和巨噬细胞效应功能
2020/01/02
摘要
背景：花生四烯酸脂质介质在2型免疫应答（过敏、哮喘）中起关键作用。而巨噬细胞是产生花生四烯酸的主要细胞，因此为2型免疫应答的关键效应细胞。我们旨在全面追踪室内尘螨（HDM）或蠕虫感染后花生四烯酸在2型免疫应答中的纵向变化并证实人类巨噬细胞中花生四烯酸重组的机制和功能。
方法：我们通过建立LC-MS/MS工作流程定量52种氧化脂以分析尘螨刺激后人单核细胞衍生的巨噬细胞（MDM）中和小鼠过敏性气道炎症（AAI）或线虫感染过程中的介体谱。通过qPCR和蛋白质印迹法测定花生四烯酸的表达，并通过多重测定评估细胞因子的产生。
结果：将肺泡样人单核细胞衍生的巨噬细胞短时程暴露（24h）在尘螨中，可抑制其5-LOX的表达及产物形成，并促进前列腺素（血栓素和前列腺素D2和E2）生成。上述花生四烯酸的重组依赖于p-38，但不依赖于Dectin-2。尘螨同样可引起促炎因子生成，但能减少人单核细胞诱导的粒细胞募集。相反，在小鼠过敏性气道炎症（AAI）或线虫感染过程中，气道中半胱氨酰白三烯（cysLT）和12- / 15-LOX代谢物呈高表达。
结论：本研究的发现表明短时间暴露于过敏原和正在进行的2型变态反应的特征是脂质介质代谢的重建，其中巨噬细胞是主要应答细胞。气道巨噬细胞中的靶向介质重建可能是预防过敏或哮喘中致病性脂质介质活化的一种可行方法。
House dust mite drives pro-inflammatory eicosanoid reprogramming and macrophage effector functions.
Henkel FDR, et al. Allergy. 2018 Dec 16.
Abstract
Background：Eicosanoid lipid mediators play key roles in type 2 immune responses,e.g. in allergy and asthma. Macrophages represent major producers of eicosanoids and they are key effector cells of type 2 immunity. We aimed to comprehensively track eicosanoid profiles during type 2 immune responses to house dust mite (HDM) or helminth infection and to identify mechanisms and functions of eicosanoid reprogramming in human macrophages.
Methods：We established an LC-MS/MS workflow for the quantification of 52 oxylipins to analyze mediator profiles in human monocyte derived macrophages (MDM) stimulated with HDM and during allergic airway inflammation (AAI) or nematode infection in mice. Expression of eicosanoid enzymes was studied by qPCR and western blot and cytokine production was assessed by multiplex assays.
Results：Short (24h) exposure of alveolar-like MDM (aMDM) to HDM suppressed 5-LOX expression and product formation, while triggering prostanoid (thromboxane and prostaglandin D2 and E2) production. This eicosanoid reprogramming was p38-dependent, but Dectin-2-independent. HDM also induced pro-inflammatory cytokine production, but reduced granulocyte recruitment by aMDM. In contrast,high levels of cysteinyl leukotrienes (cysLTs) and 12-/15-LOX metabolites were produced in the airways during AAI or nematode infection in mice.
Conclusion：Our findings show that a short exposure to allergens as well as ongoing type 2 immune responses are characterized by a fundamental reprogramming of the lipid mediator metabolism with macrophages representing particularly plastic responder cells. Targeting mediator reprogramming in airway macrophages may represent a viable approach to prevent pathogenic lipid mediator profiles in allergy or asthma. This article is protected by copyright. All rights reserved.
背景：花生四烯酸脂质介质在2型免疫应答（过敏、哮喘）中起关键作用。而巨噬细胞是产生花生四烯酸的主要细胞，因此为2型免疫应答的关键效应细胞。我们旨在全面追踪室内尘螨（HDM）或蠕虫感染后花生四烯酸在2型免疫应答中的纵向变化并证实人类巨噬细胞中花生四烯酸重组的机制和功能。
方法：我们通过建立LC-MS/MS工作流程定量52种氧化脂以分析尘螨刺激后人单核细胞衍生的巨噬细胞（MDM）中和小鼠过敏性气道炎症（AAI）或线虫感染过程中的介体谱。通过qPCR和蛋白质印迹法测定花生四烯酸的表达，并通过多重测定评估细胞因子的产生。
结果：将肺泡样人单核细胞衍生的巨噬细胞短时程暴露（24h）在尘螨中，可抑制其5-LOX的表达及产物形成，并促进前列腺素（血栓素和前列腺素D2和E2）生成。上述花生四烯酸的重组依赖于p-38，但不依赖于Dectin-2。尘螨同样可引起促炎因子生成，但能减少人单核细胞诱导的粒细胞募集。相反，在小鼠过敏性气道炎症（AAI）或线虫感染过程中，气道中半胱氨酰白三烯（cysLT）和12- / 15-LOX代谢物呈高表达。
结论：本研究的发现表明短时间暴露于过敏原和正在进行的2型变态反应的特征是脂质介质代谢的重建，其中巨噬细胞是主要应答细胞。气道巨噬细胞中的靶向介质重建可能是预防过敏或哮喘中致病性脂质介质活化的一种可行方法。
(中国医科大学附属一院呼吸与危重症学科 李文扬 摘译 杨冬 审校)
(Henkel FDR, et al. Allergy. 2018 Dec 16.)
(Henkel FDR, et al. Allergy. 2018 Dec 16.)
House dust mite drives pro-inflammatory eicosanoid reprogramming and macrophage effector functions.
Henkel FDR, et al. Allergy. 2018 Dec 16.
Abstract
Background：Eicosanoid lipid mediators play key roles in type 2 immune responses,e.g. in allergy and asthma. Macrophages represent major producers of eicosanoids and they are key effector cells of type 2 immunity. We aimed to comprehensively track eicosanoid profiles during type 2 immune responses to house dust mite (HDM) or helminth infection and to identify mechanisms and functions of eicosanoid reprogramming in human macrophages.
Methods：We established an LC-MS/MS workflow for the quantification of 52 oxylipins to analyze mediator profiles in human monocyte derived macrophages (MDM) stimulated with HDM and during allergic airway inflammation (AAI) or nematode infection in mice. Expression of eicosanoid enzymes was studied by qPCR and western blot and cytokine production was assessed by multiplex assays.
Results：Short (24h) exposure of alveolar-like MDM (aMDM) to HDM suppressed 5-LOX expression and product formation, while triggering prostanoid (thromboxane and prostaglandin D2 and E2) production. This eicosanoid reprogramming was p38-dependent, but Dectin-2-independent. HDM also induced pro-inflammatory cytokine production, but reduced granulocyte recruitment by aMDM. In contrast,high levels of cysteinyl leukotrienes (cysLTs) and 12-/15-LOX metabolites were produced in the airways during AAI or nematode infection in mice.
Conclusion：Our findings show that a short exposure to allergens as well as ongoing type 2 immune responses are characterized by a fundamental reprogramming of the lipid mediator metabolism with macrophages representing particularly plastic responder cells. Targeting mediator reprogramming in airway macrophages may represent a viable approach to prevent pathogenic lipid mediator profiles in allergy or asthma. This article is protected by copyright. All rights reserved.
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