Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis
Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis
复制标题
组织蛋白酶 G 裂解并激活 IL-36γ 并促进银屑病炎症
DOI：
10.2147/dddt.s194765
复制
发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Yin, ZhiQiang
中科院分区：
文献类型：
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作者：
Guo, Jing;Tu, Jie;Yin, ZhiQiang
背景：IL-36 γ被认为是银屑病患者中一种有价值的生物标志物，它作为一种非活性前体表达，需要进行蛋白水解加工和激活，中性粒细胞衍生的蛋白酶似乎是IL-36 γ的有效激活酶。目的：研究组织蛋白酶G （CG）和中性粒细胞弹性酶（NE）对IL-36 γ的激活作用。材料和方法：采用重组无活性全长(FL)-IL-36 γ结合不同剂量的NE或CG刺激HaCaT细胞；制备中性粒细胞胞外陷阱（NETs），作用于FL-IL-36 γ，然后刺激HaCaT细胞。采用实时定量PCR和ELISA检测CXCL-1和CXCL-8的表达。我们建立了吡喹莫德诱导的银屑病样小鼠模型，以评价皮下注射中性粒细胞衍生蛋白酶或其抑制剂的效果。采用组织病理学和免疫印迹法进行疗效评价。结果：纯化的CG裂解和激活重组人FL-IL-36 γ，促进人角质形成细胞CXCL-1和CXC -8的表达，NETs激活FL-IL-36 γ，并被serpin A3抑制。CG诱导小鼠银屑病样病变中IL-36 γ的表达更短，加重了咪喹莫特诱导的银屑病样病变，而重组serpin A3则减轻了银屑病样小鼠模式的严重程度。结论：CG具有裂解和激活IL-36 γ的能力，可加重吡喹莫德诱导的小鼠银屑病病变。因此，cg特异性抑制剂可能是治疗银屑病的有希望的药物。
Background: IL-36 gamma is considered to be a valuable biomarker in psoriatic patients, which is expressed as an inactive precursor that needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36 gamma.Objectives: This study aims to investigate the activation of IL-36 gamma by cathepsin G (CG) and neutrophil elastase (NE).Materials and methods: We used inactive recombinant full-length (FL)-IL-36 gamma with different doses of NE or CG to stimulate HaCaT cells; neutrophil extracellular traps (NETs) were prepared to act on FL-IL-36 gamma and then stimulate HaCaT cells. Real-time quantitative PCR and ELISA were performed to detect CXCL-1 and CXCL-8 expression. We developed imiquimod-induced psoriasis-like mouse model to evaluate the effect of hypodermic injection of neutrophil-derived protease or its inhibitor. Histopathology and Western blotting were conducted for effect assessment.Results: Purified CG cleaved and activated recombinant human FL-IL-36 gamma to promote CXCL-1 and CXC L-8 expression by human keratinocytes, and NETs activated FL-IL-36 gamma and the activation was inhibited by serpin A3. CG induced expression of a more truncated IL-36 gamma in psoriasiform lesion of mice and aggravated the psoriasis-like lesion induced by imiquimod, whereas recombinant serpin A3 alleviated the severity of the psoriasis-like mouse mode.Conclusion: CG has the ability to cleave and activate IL-36 gamma and aggravate imiquimod-induced mouse psoriasilbrm lesion. Thus, CG-specific inhibitors might be promising therapeutic drugs for psoriasis.