Galvão Izabela, Queiroz-Junior Celso Martins, de Oliveira Vivian Louise Soares, Pinho Vanessa, Hirsch Emilio, Teixeira Mauro Martins
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Pharmacol. 2019 Jan 7;9:1505. doi: 10.3389/fphar.2018.01505. eCollection 2018.
Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice. Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-γ (AS605240) or PI3Kδ (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1β levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3Kγ or PI3Kδ reduced Nuclear Factor kappa B (NF-κB) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3Kγ or PI3Kδ selective inhibitors alone. Taken together, these results suggest that neutrophils can use PI3Kγ or PI3Kδ to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout.
磷脂酰肌醇-3激酶（PI3Ks）是关键的信号酶，参与免疫细胞功能的多个方面。PI3Kγ和PI3Kδ是白细胞中表达的主要亚型。PI3K亚型在炎症消退中的作用仍知之甚少。在此，我们在小鼠痛风模型中研究了PI3Kγ和PI3Kδ对炎症消退的作用。实验在野生型雄性C57/Bl6小鼠中进行。在注射MSU晶体12小时后，即在炎症高峰期，将PI3K-γ（AS605240）或PI3Kδ（GSK045）的选择性抑制剂注射到关节中。抑制任一PI3K亚型均可减少因注射MSU晶体而迁移的中性粒细胞数量。这与关节周围组织中髓过氧化物酶活性和IL-1β水平的降低以及组织学评分的降低有关。通过机械性痛觉过敏降低所观察到的关节功能障碍，用任一抑制剂治疗均可改善。中性粒细胞数量的减少与这些细胞凋亡和吞噬作用的增强有关。炎症消退间隔缩短，表明抑制任一亚型均可诱导嗜中性炎症的消退。PI3Kγ或PI3Kδ的阻断降低了核因子κB（NF-κB）的激活。泛PI3K抑制剂（CL27c）减轻MSU晶体诱导的炎症的程度与单独使用PI3Kγ或PI3Kδ选择性抑制剂所达到的程度相似。综上所述，这些结果表明中性粒细胞可利用PI3Kγ或PI3Kδ留在腔内，阻断任一同工酶足以诱导其凋亡并在小鼠痛风模型中消退炎症。
