Carbonic anhydrase enzymes regulate mast cell-mediated inflammation
Carbonic anhydrase enzymes regulate mast cell-mediated inflammation
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DOI：
10.1084/jem.20151739
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发表时间：
2016-08-22
影响因子：
15.3
通讯作者：
Siracusa, Mark C.
中科院分区：
文献类型：
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作者：
Henry, Everett K.;Sy, Chandler B.;Siracusa, Mark C.
2型细胞因子反应是发展对寄生虫的保护性免疫所必需的，但也引起与过敏和哮喘相关的炎症。最近的研究发现，外周造血祖细胞通过增强发育为肥大细胞的能力，有助于2型细胞因子介导的炎症。在这项研究中，我们发现碳酸酐酶（Car）酶在2型相关祖细胞中上调，并证明Car酶抑制足以防止旋毛虫感染或诱导食物过敏样疾病后小鼠肥大细胞的反应和炎症。此外，我们使用了CRI SPR/Cas9技术，并证明基因编辑Car1足以选择性地减少肥大细胞的发育。最后，我们证明Car酶可以靶向阻止人类肥大细胞的发育。总的来说，这些实验确定了Car酶在调节肥大细胞谱系承诺方面的一个以前未被认识到的作用，并表明Car酶抑制剂可能具有治疗肥大细胞介导的炎症的潜力。
Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy-like disease. Further, we used CRI SPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell-mediated inflammation.