International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 818 West 10th Ave., Vancouver V5Z 1M9, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver V6T 2B5, BC, Canada.
International Collaboration On Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 818 West 10th Ave., Vancouver V5Z 1M9, BC, Canada.
Matrix Biol. 2019 Jan;75-76:126-140. doi: 10.1016/j.matbio.2017.12.005. Epub 2017 Dec 14.
Granzyme B (GzmB) is a serine protease emerging as an important mediator of skin injury, inflammation and repair. Found at low levels in healthy skin, GzmB is dramatically elevated in chronic disease and inflammatory skin disorders, including diabetic ulcers, hypertrophic scarring, autoimmune skin disorders, cutaneous leishmaniasis and aging skin. Traditionally known for its pro-apoptotic function, the role of GzmB in disease has been redefined due to the discovery of additional activities involving the cleavage of extracellular matrix proteins, epithelial barrier disruption, fibrosis, vascular permeability, anoikis, inflammation and autoimmunity. In addition to the accumulation of GzmB cells in diseased tissue, and critical to the mechanistic redefinition, is the realization that GzmB often accumulates in the extracellular milieu, retains its activity in plasma, and is expressed by both immune and non-immune cells that may or may not express perforin, the pore-forming protein required for GzmB internalization into target cells. As GzmB is not normally found in the extracellular milieu, and does not appear to be regulated, GzmB-mediated proteolysis can impact processes such as tissue remodelling, barrier function, autoantigen generation and angiogenesis. The present review will summarize and critically examine the current knowledge regarding GzmB in inflammatory skin disease, providing an overview of both apoptotic and extracellular mechanisms, but with a focus on the extracellular roles of GzmB in skin health and disease.
颗粒酶 B（GzmB）是一种丝氨酸蛋白酶，作为皮肤损伤、炎症和修复的重要介质而出现。在健康皮肤中含量较低，但在慢性疾病和炎症性皮肤病中显著升高，包括糖尿病溃疡、肥厚性瘢痕、自身免疫性皮肤病、皮肤利什曼病和衰老皮肤。GzmB 传统上以其促凋亡功能而闻名，但由于发现了涉及细胞外基质蛋白切割、上皮屏障破坏、纤维化、血管通透性、失巢凋亡、炎症和自身免疫等额外活性，其在疾病中的作用已被重新定义。除了在疾病组织中 GzmB 细胞的积累，以及对机制重新定义至关重要的是，人们意识到 GzmB 通常在细胞外环境中积累，在血浆中保持其活性，并由免疫和非免疫细胞表达，这些细胞可能表达或不表达穿孔素，这是 GzmB 内化进入靶细胞所需的形成孔的蛋白。由于 GzmB 通常不在细胞外环境中发现，并且似乎不受调节，因此 GzmB 介导的蛋白水解可以影响组织重塑、屏障功能、自身抗原产生和血管生成等过程。本文综述总结并批判性地审查了 GzmB 在炎症性皮肤病中的最新知识，概述了凋亡和细胞外机制，但重点是 GzmB 在皮肤健康和疾病中的细胞外作用。
