Mast Cell Peptidases Chameleons of Innate Immunity and Host Defense
Mast Cell Peptidases Chameleons of Innate Immunity and Host Defense
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DOI：
10.1165/rcmb.2009-0324rt
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发表时间：
2010-03-01
影响因子：
6.4
通讯作者：
Caughey, George H.
中科院分区：
文献类型：
--
作者：
Trivedi, Neil N.;Caughey, George H.
肥大细胞产生并分泌大量的肽酶，这些肽酶以颗粒的形式大量储存，它们构成了所有细胞蛋白质的高部分。也许没有其他免疫细胞被如此慷慨地赋予肽酶。在首次描述主要肽酶后的许多年里，它们最为人所知的是作为脱粒的标志物，因为它们响应肥大细胞刺激而局部释放，并且可以全身分布并在血液中检测到。主要的肽酶是类胰蛋白酶、糜蛋白酶、羧肽酶A3和二肽基肽酶I（组织蛋白酶C）。许多研究表明，这些酶是重要的，甚至是至关重要的宿主防御和稳态。内源性和过敏原或病原体相关的目标已经确定。与肽酶作为促炎剂的狭义概念不同，几种肽酶限制了内源性肽和毒液的炎症和毒性。肽酶是相互依赖的，因此一种酶的缺失或失活可以改变其他酶的水平和活性。哺乳动物的肥大细胞肽酶，特别是糜酶和胰蛋白酶，在数量、表达、生物物理特性和特异性上有很大的不同，也许是因为它们在它们帮助击退的病原体的压力下过度进化。类胰蛋白酶和糜蛋白酶参与某些病理刺激了用于哮喘、肺纤维化、肺动脉高压、溃疡性结肠炎和心血管疾病的治疗性抑制剂的开发。虽然动物研究支持肥大细胞肽酶抑制剂减轻某些疾病的潜力，但其他研究（如在缺乏选定肽酶的小鼠中）预测了其在防御细菌和寄生虫方面的作用，并且全身失活可能会损害宿主防御。
Mast cells make and secrete an abundance of peptidases, which are stored in such large amounts in granules that they comprise a high fraction of all cellular protein. Perhaps no other immune cell is so generously endowed with peptidases. For many years after the main peptidases were first described, they were best known as markers of degranulation, for they are released locally in response to mast cell stimulation and can be distributed systemically and detected in blood. The principal peptidases are tryptases, chymases, carboxypeptidase A3, and dipeptidylpepticlase I (cathepsin C). Numerous studies suggest that these enzymes are important and even critical for host defense and homeostasis. Endogenous and allergen or pathogen-associated targets have been identified. Belying the narrow notion of peptidases as proinflammatory, several of the peptidases limit inflammation and toxicity of endogenous peptides and venoms. The peptidases are interdependent, so that absence or inactivity of one enzyme can alter levels and activity of others. Mammalian mast cell peptidases-chymases and tryptases especially-vary remarkably in number, expression, biophysical properties, and specificity, perhaps because they hyper-evolved under pressure from the very pathogens they help to repel. Tryptase and chymase involvement in some pathologies stimulated development of therapeutic inhibitors for use in asthma, lung fibrosis, pulmonary hypertension, ulcerative colitis, and cardiovascular diseases. While animal studies support the potential for mast cell peptidase inhibitors to mitigate certain diseases, other studies, as in mice lacking selected peptidases, predict roles in defense against bacteria and parasites and that systemic inactivation may impair host defense.