CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma.
CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma.
复制标题
在哮喘小鼠模型中，CB2受体调节限制过敏性气道炎症的自然杀伤细胞。
作者：
Ferrini ME;Hong S;Stierle A;Stierle D;Stella N;Roberts K;Jaffar Z
过敏性哮喘是一种慢性气道炎症性疾病，涉及先天性和适应性免疫反应的互补作用。内源性产生的大麻素通过CB 2受体起作用，在体内平衡和炎症过程中发挥重要作用。然而，CB 2作用类花生酸对常见屋尘螨（HDM）过敏原致敏之前的先天事件的贡献仍有待阐明。我们研究了CB 2活化在变应原诱导的肺部炎症和NK细胞效应功能中的作用。在鼻内暴露于HDM过敏原后，检查了CB 2缺陷型（CB 2 −/−）小鼠的肺粘膜反应，并与野生型同窝小鼠进行了比较。缺乏CB 2受体的小鼠表现出肺自然杀伤（NK）细胞数量增加，但对过敏性炎症的诱导具有抗性，例如吸入过敏原后气道嗜酸性粒细胞增多、2型细胞因子产生和粘液分泌减少。当用CB 2特异性拮抗剂处理WT小鼠时，这种现象得到证实，所述拮抗剂引起对HDM诱导的气道炎症和杯状细胞增生的显著抑制。出乎意料的是，CB 2 −/−小鼠肺部NK细胞的优势与第2组先天淋巴细胞（ILC 2）数量的减少相关。NK细胞的耗竭恢复了肺中的过敏原反应性，并与ILC 2数量升高相关。总的来说，这些结果表明，CB 2激活是至关重要的，在调节肺NK细胞功能，并表明NK细胞用于限制ILC 2激活和随后的过敏性气道炎症。CB 2抑制可能是调节肺部炎症过程中NK细胞反应的重要靶点。
Allergic asthma is a chronic airway inflammatory disease involving the complementary actions of innate and adaptive immune responses. Endogenously generated cannabinoids, acting via CB2 receptors play important roles in both homeostatic and inflammatory processes. However, the contribution of CB2-acting eicosanoids to the innate events preceding sensitization to the common house dust mite (HDM) allergen, remain to be elucidated. We investigated the role of CB2 activation during allergen-induced pulmonary inflammation and NK cell effector function. Lung mucosal responses in CB2-deficient (CB2−/−) mice were examined and compared with wild type littermates following intranasal exposure to HDM allergen. Mice lacking CB2 receptors exhibited elevated numbers of pulmonary natural killer (NK) cells yet were resistant to the induction of allergic inflammation exemplified by diminished airway eosinophilia, type 2 cytokine production and mucus secretion after allergen inhalation. This phenomenon was corroborated when WT mice were treated with a CB2-specific antagonist that caused a pronounced inhibition of HDM-induced airway inflammation and goblet cell hyperplasia. Unexpectedly, the preponderance of NK cells in the lungs of CB2−/− mice correlated with reduced numbers of group 2 innate lymphoid cells (ILC2s). Depletion of NK cells restored the allergen responsiveness in the lungs and was associated with elevated ILC2 numbers. Collectively, these results reveal that CB2 activation is crucial in regulating pulmonary NK cell function, and suggest that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation.