Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK.
Sci Adv. 2017 Aug 16;3(8):e1700898. doi: 10.1126/sciadv.1700898. eCollection 2017 Aug.
Vomocytosis, or nonlytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date, the host signaling events that underpin expulsion remain entirely unknown. We use a targeted inhibitor screen to identify the MAP kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages, whereas stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host signaling regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies.
出胞作用，或非裂解性外排，是一种人们尚未充分了解的过程，巨噬细胞通过该过程将未能杀死的活病原体重新释放到细胞外环境中。出胞作用在脊椎动物中是保守的，并且与多种病原体有关，但迄今为止，支持排出的宿主信号事件仍然完全未知。我们使用靶向抑制剂筛选来鉴定 MAP 激酶 ERK5 作为出胞作用的关键抑制剂。ERK5 活性的药理学抑制或遗传操作可显著提高人巨噬细胞的出胞作用率，而 ERK5 信号通路的刺激则抑制出胞作用。最后，我们使用隐球菌病的斑马鱼模型表明，体内降低 ERK5 活性会刺激出胞作用，导致感染的传播减少。因此，ERK5 是第一个被鉴定为出胞作用的宿主信号调节剂，也是未来开发出胞作用调节治疗的潜在靶点。
