Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
Cells. 2019 Aug 23;8(9):964. doi: 10.3390/cells8090964.
Uncontrolled inflammation leads to tissue damage and it is central for the development of chronic inflammatory diseases and autoimmunity. An acute inflammatory response is finely regulated by the action of anti-inflammatory and pro-resolutive mediators, culminating in the resolution of inflammation and restoration of homeostasis. There are few studies investigating intracellular signaling pathways associated with the resolution of inflammation. Here, we investigate the role of Rho-associated kinase (ROCK), a serine/threonine kinase, in a model of self-resolving neutrophilic inflammatory. We show that ROCK activity, evaluated by P-MYPT-1 kinetics, was higher during the peak of lipopolysaccharide-induced neutrophil influx in the pleural cavity of mice. ROCK inhibition by treatment with Y-27632 decreased the accumulation of neutrophils in the pleural cavity and was associated with an increase in apoptotic events and efferocytosis, as evaluated by an in vivo assay. In a model of gout, treatment with Y-27632 reduced neutrophil accumulation, IL-1β levels and hypernociception in the joint. These were associated with reduced MYPT and IκBα phosphorylation levels and increased apoptosis. Finally, inhibition of ROCK activity also induced apoptosis in human neutrophils and destabilized cytoskeleton, extending the observed effects to human cells. Taken together, these data show that inhibition of the ROCK pathway might represent a potential therapeutic target for neutrophilic inflammatory diseases.
失控的炎症会导致组织损伤，是慢性炎症性疾病和自身免疫的发展的核心。急性炎症反应通过抗炎和促分解介质的作用得到精细调节，最终导致炎症的消退和内稳态的恢复。目前很少有研究调查与炎症消退相关的细胞内信号通路。在这里，我们研究了 Rho 相关激酶（ROCK）在自限性嗜中性粒细胞炎症模型中的作用。我们发现，在小鼠胸腔内脂多糖诱导的嗜中性粒细胞浸润高峰时，通过 P-MYPT-1 动力学评估的 ROCK 活性更高。用 Y-27632 治疗抑制 ROCK 活性可减少胸腔内嗜中性粒细胞的积聚，并与体内试验评估的凋亡事件和吞噬作用增加相关。在痛风模型中，用 Y-27632 治疗可减少关节内中性粒细胞的积聚、IL-1β 水平和超敏反应，这与 MYPT 和 IκBα 磷酸化水平降低以及凋亡增加有关。最后，抑制 ROCK 活性也可诱导人中性粒细胞凋亡并破坏细胞骨架，将观察到的效应扩展到人类细胞。总之，这些数据表明抑制 ROCK 通路可能是治疗嗜中性粒细胞炎症性疾病的潜在治疗靶点。
