International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, British Columbia, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Physiol Cell Physiol. 2022 Jul 1;323(1):C170-C189. doi: 10.1152/ajpcell.00052.2022. Epub 2022 Apr 20.
The predominant function of the skin is to serve as a barrier-to protect against external insults and to prevent water loss. Junctional and structural proteins in the stratum corneum, the outermost layer of the epidermis, are critical to the integrity of the epidermal barrier as it balances ongoing outward migration, differentiation, and desquamation of keratinocytes in the epidermis. As such, epidermal barrier function is highly susceptible to upsurges of proteolytic activity in the stratum corneum and epidermis. Granzyme B is a serine protease scarce in healthy tissues but present at high levels in tissues encumbered by chronic inflammation. Discovered in the 1980s, granzyme B is currently recognized for its intracellular roles in immune cell-mediated apoptosis as well as extracellular roles in inflammation, chronic injuries, tissue remodeling, as well as processing of cytokines, matrix proteins, and autoantigens. Increasing evidence has emerged in recent years supporting a role for granzyme B in promoting barrier dysfunction in the epidermis by direct cleavage of barrier proteins and eliciting immunoreactivity. Likewise, granzyme B contributes to impaired epithelial function of the airways, retina, gut, and vessels. In the present review, the role of granzyme B in cutaneous epithelial dysfunction is discussed in the context of specific conditions with an overview of underlying mechanisms as well as utility of current experimental and therapeutic inhibitors.
皮肤的主要功能是作为屏障——保护身体免受外界伤害，并防止水分流失。角质层是表皮的最外层，其中的连接蛋白和结构蛋白对于表皮屏障的完整性至关重要，因为它平衡了表皮中角质形成细胞的持续向外迁移、分化和脱落。因此，表皮屏障功能非常容易受到角质层和表皮中蛋白水解活性激增的影响。颗粒酶 B 是一种丝氨酸蛋白酶，在健康组织中含量很少，但在慢性炎症受累的组织中含量很高。颗粒酶 B 于 20 世纪 80 年代被发现，目前被认为在免疫细胞介导的细胞凋亡中具有细胞内作用，以及在炎症、慢性损伤、组织重塑以及细胞因子、基质蛋白和自身抗原的加工中具有细胞外作用。近年来，越来越多的证据表明，颗粒酶 B 通过直接切割屏障蛋白和引发免疫反应，在促进表皮屏障功能障碍方面发挥作用。同样，颗粒酶 B 也会导致气道、视网膜、肠道和血管的上皮功能障碍。在本综述中，将讨论颗粒酶 B 在特定情况下的皮肤上皮功能障碍中的作用，概述潜在的机制以及当前实验和治疗抑制剂的应用。
