金黄色葡萄球菌通过 V8 蛋白酶-PAR1 轴驱动瘙痒和搔抓诱导的皮肤损伤。
S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.
机构信息
Department of Immunology, Harvard Medical School, Boston, MA 02215, USA.
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
出版信息
Cell. 2023 Nov 22;186(24):5375-5393.e25. doi: 10.1016/j.cell.2023.10.019.
Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.
痒是一种不愉快的感觉，会引起搔抓的欲望。皮肤屏障不断暴露于微生物及其产物中。然而，微生物在瘙痒产生中的作用尚不清楚。在这里，我们表明金黄色葡萄球菌，一种与瘙痒性皮肤病相关的细菌病原体，可直接激活痒觉感受器感觉神经元以引发瘙痒。表皮金黄色葡萄球菌暴露会引起强烈的瘙痒和搔抓诱导的损伤。通过测试多种具有毒力因子的同源细菌突变体，我们确定金黄色葡萄球菌丝氨酸蛋白酶 V8 是引发自发性瘙痒和异感的关键介质。V8 切割小鼠和人感觉神经元上的蛋白酶激活受体 1（PAR1）。通过基因缺失、小干扰 RNA（siRNA）敲低或药理学阻断靶向 PAR1 可减少 V8 和金黄色葡萄球菌暴露引起的瘙痒和皮肤损伤。因此，我们确定了一种潜在的瘙痒性细菌因子的作用机制，并证明了抑制 V8-PAR1 信号传导治疗瘙痒的潜力。
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