International Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Front Immunol. 2024 Jun 5;15:1398120. doi: 10.3389/fimmu.2024.1398120. eCollection 2024.
Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity.
银屑病是一种具有全身表现的炎症性疾病，最常见的表现为伸肌表面有瘙痒、红斑、鳞屑的斑块。白细胞介素-23/白细胞介素-17 促炎信号通路的激活是银屑病的标志，其抑制是临床管理的关键。颗粒酶 K（GzmK）是一种免疫细胞分泌的丝氨酸蛋白酶，在炎症和增殖性皮肤疾病中升高。在本研究中，与非皮损性银屑病和健康对照组皮肤相比，人银屑病皮损中 GzmK 水平升高。在咪喹莫特（IMQ）诱导的银屑病的既定小鼠模型中，GzmK 的基因缺失显著降低了疾病严重程度，表现在斑块形成延迟、红斑和脱屑减少、表皮厚度和炎症浸润减少。分子特征表明，GzmK 有助于巨噬细胞分泌白细胞介素-23 以及 PAR-1 依赖性角质形成细胞增殖。这些发现表明，GzmK 增强了白细胞介素-23 驱动的炎症以及角质形成细胞增殖，从而加重银屑病的严重程度。
