Shpacovitch Victoria M, Seeliger Stephan, Huber-Lang Markus, Balkow Sandra, Feld Micha, Hollenberg Morley D, Sarma Vidya J, Ward Peter A, Strey Anke, Gerke Volker, Sommerhoff Christian P, Vergnolle Nathalie, Steinhoff Martin
Department of Dermatology, IZKF Münster, and Boltzmann Institute for Immunobiology of the Skin, University of Münster, Germany.
Exp Dermatol. 2007 Oct;16(10):799-806. doi: 10.1111/j.1600-0625.2007.00605.x.
Skin is the first barrier preventing microorganism invasion in host. Wounds destroy this defense barrier and, without an appropriate care, may lead to sepsis. Neutrophil activation and immigration plays an important role at the inflammatory stage of wound healing. Neutrophils are known to express proteinase-activated receptors (PARs), which can be activated by serine proteases, also by enzymes involved in wound healing. We previously reported that PAR(2) agonists up-regulate cell adhesion molecule expression and cytokine production by human neutrophils. Here, we demonstrate that PAR(2) agonists (serine proteases as well as synthetic peptides) reduce transendothelial migration of neutrophils and prolong their life in vitro. Synthetic PAR(2) agonist also enhanced protective interferon (IFN)gamma-induced FcgammaRI expression at neutrophil cell surface. Of note, IFNgamma is a cytokine, which was used in clinical trials to reactivate human neutrophil functions during sepsis. Moreover, we observed a significant increase of PAR(2) expression on cell surface of neutrophils from septic patients as compared with healthy volunteers. Together, our results indicate that PAR(2) may be involved in the pathophysiology of neutrophil-endothelial interactions during wound healing or later during sepsis in humans, potentially by affecting neutrophil apoptosis, transendothelial migration and Fcgamma receptor-mediated phagocytosis.
皮肤是宿主抵御微生物入侵的第一道屏障。伤口破坏了这一防御屏障，若没有适当的护理，可能会导致败血症。中性粒细胞的激活和迁移在伤口愈合的炎症阶段起着重要作用。已知中性粒细胞表达蛋白酶激活受体（PARs），其可被丝氨酸蛋白酶激活，也可被参与伤口愈合的酶激活。我们之前报道过PAR(2)激动剂可上调人中性粒细胞的细胞黏附分子表达和细胞因子产生。在此，我们证明PAR(2)激动剂（丝氨酸蛋白酶以及合成肽）可减少中性粒细胞的跨内皮迁移并延长其体外存活时间。合成的PAR(2)激动剂还增强了保护性干扰素（IFN）γ诱导的中性粒细胞表面FcγRI表达。值得注意的是，IFNγ是一种细胞因子，在临床试验中被用于在败血症期间重新激活人类中性粒细胞功能。此外，我们观察到与健康志愿者相比，脓毒症患者中性粒细胞表面PAR(2)表达显著增加。总之，我们的结果表明PAR(2)可能参与人类伤口愈合期间或之后脓毒症期间中性粒细胞与内皮细胞相互作用的病理生理学过程，可能是通过影响中性粒细胞凋亡、跨内皮迁移和Fcγ受体介导的吞噬作用。
