Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Uppsala, Sweden.
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Front Immunol. 2022 Jul 5;13:918305. doi: 10.3389/fimmu.2022.918305. eCollection 2022.
Proteases are stored in very large amounts within abundant cytoplasmic granules of mast cells (MCs), and in lower amounts in basophils. These proteases are stored in their active form in complex with negatively charged proteoglycans, such as heparin and chondroitin sulfate, ready for rapid release upon MC and basophil activation. The absolute majority of these proteases belong to the large family of chymotrypsin related serine proteases. Three such enzymes are found in human MCs, a chymotryptic enzyme, the chymase, a tryptic enzyme, the tryptase and cathepsin G. Cathepsin G has in primates both chymase and tryptase activity. MCs also express a MC specific exopeptidase, carboxypeptidase A3 (CPA3). The targets and thereby the functions of these enzymes have for many years been the major question of the field. However, the fact that some of these enzymes have a relatively broad specificity has made it difficult to obtain reliable information about the biologically most important targets for these enzymes. Under optimal conditions they may cleave a relatively large number of potential targets. Three of these enzymes, the chymase, the tryptase and CPA3, have been shown to inactivate several venoms from snakes, scorpions, bees and Gila monster. The chymase has also been shown to cleave several connective tissue components and thereby to be an important player in connective tissue homeostasis. This enzyme can also generate angiotensin II (Ang II) by cleavage of Ang I and have thereby a role in blood pressure regulation. It also display anticoagulant activity by cleaving fibrinogen and thrombin. A regulatory function on excessive T2 immunity has also been observed for both the chymase and the tryptase by cleavage of a highly selective set of cytokines and chemokines. The chymase also appear to have a protective role against ectoparasites such as ticks, mosquitos and leeches by the cleavage of their anticoagulant proteins. We here review the data that has accumulated concerning the potential functions of these enzymes and we discuss how this information sheds new light on the role of MCs and basophils in health and disease.
蛋白酶以与带负电荷的蛋白聚糖（如肝素和硫酸软骨素）复合物的形式大量储存在肥大细胞（MCs）丰富的细胞质颗粒中，在嗜碱性粒细胞中含量较低。这些蛋白酶以其活性形式储存在复合物中，准备在 MC 和嗜碱性粒细胞激活时迅速释放。这些蛋白酶绝大多数属于糜蛋白酶相关丝氨酸蛋白酶大家族。人类 MCs 中发现了三种这样的酶，一种糜蛋白酶、糜蛋白酶，一种胰蛋白酶、胰蛋白酶和组织蛋白酶 G。在灵长类动物中，组织蛋白酶 G 既有糜蛋白酶活性，也有胰蛋白酶活性。MCs 还表达一种 MC 特异性外肽酶，羧肽酶 A3（CPA3）。这些酶的靶标及其功能多年来一直是该领域的主要问题。然而，事实上，这些酶中的一些具有相对广泛的特异性，这使得很难获得关于这些酶的生物学上最重要靶标的可靠信息。在最佳条件下，它们可能会切割相对大量的潜在靶标。其中三种酶，糜蛋白酶、胰蛋白酶和 CPA3，已被证明能使蛇、蝎子、蜜蜂和吉拉毒蜥的几种毒液失活。糜蛋白酶还被证明能切割几种结缔组织成分，因此是结缔组织动态平衡的重要参与者。这种酶还可以通过切割血管紧张素 I 生成血管紧张素 II（Ang II），从而在血压调节中发挥作用。它还通过切割纤维蛋白原和凝血酶具有抗凝活性。糜蛋白酶和胰蛋白酶通过切割一组高度选择性的细胞因子和趋化因子，对过度的 T2 免疫也显示出调节作用。糜蛋白酶似乎还通过切割其抗凝蛋白对蜱、蚊子和水蛭等外寄生虫具有保护作用。我们在这里回顾了有关这些酶潜在功能的累积数据，并讨论了这些信息如何为 MCs 和嗜碱性粒细胞在健康和疾病中的作用提供新的见解。
