Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
Christine Kühne - Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
Allergy. 2017 Dec;72(12):1925-1935. doi: 10.1111/all.13227. Epub 2017 Jun 30.
Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H R). The aim of this study was to determine the role of H R in modulating lung inflammatory responses.
H R was blocked using famotidine or activated using dimaprit in both the ovalbumin (OVA) and house dust mite extract (HDM) murine models of respiratory inflammation. H R-deficient animals and CD1d/H R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGalCer or OCH) to invariant natural killer T (iNKT) cells.
Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway diseases were more severe in H R-deficient animals. Flow cytometric analysis of lung tissue from H R-deficient animals revealed increased numbers of CD1d dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer-stimulated iNKT cells from H R-deficient mice secreted higher levels of IL-4, IL-5, and GM-CSF. In vivo, αGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H R-deficient (CD1d H R ) animals normalized the lung response to HDM.
The deliberate activation of H R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.
组胺是一种关键的免疫调节介质，可通过激活组胺受体 2（H R）来抑制促炎反应。本研究旨在确定 H R 在调节肺部炎症反应中的作用。
在卵清蛋白（OVA）和屋尘螨提取物（HDM）两种呼吸道炎症的小鼠模型中，使用法莫替丁阻断 H R 或使用二甲普瑞激活 H R。利用 H R 缺陷型动物和 CD1d/H R 缺陷型动物，研究脂质抗原（αGalCer 或 OCH）对不变自然杀伤 T（iNKT）细胞的 CD1d 呈递作用。
法莫替丁治疗导致 OVA 模型中更严重的气道疾病，而二甲普瑞治疗则显著降低疾病严重程度。OVA 和 HDM 诱导的气道疾病在 H R 缺陷型动物中更为严重。H R 缺陷型动物肺组织的流式细胞术分析显示，CD1d 树突状细胞数量增加，iNKT 细胞数量增加。体外实验表明，H R 缺陷型小鼠的αGalCer 刺激的 iNKT 细胞分泌更高水平的 IL-4、IL-5 和 GM-CSF。体内实验中，αGalCer 或 OCH 给药到肺部可增强 H R 缺陷型或法莫替丁处理动物的黏液分泌、炎症细胞募集和细胞因子产生，而二甲普瑞则抑制 H R 缺陷型肺 iNKT 细胞对αGalCer 的反应。在 H R 缺陷型（CD1d H R ）动物中去除 iNKT 细胞可使对 HDM 的肺部反应正常化。
故意激活 H R 或其下游信号分子可能成为慢性肺部炎症性疾病的一种新的治疗靶点，特别是当 CD1d 介导的脂质抗原呈递给 iNKT 细胞导致发病机制时。
