Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Pharmacol Res. 2021 Mar;165:105445. doi: 10.1016/j.phrs.2021.105445. Epub 2021 Jan 22.
The resolution of inflammation is a dynamic process, characterized by the biosynthesis of pro-resolving mediators, including the lipid Lipoxin A4 (LXA). LXA acts on the N-formyl peptide receptor 2 (FPR2/ALX) to mediate anti-inflammatory and pro-resolving effects. In order to exploit the therapeutic potential of endogenous LXA in the context of inflammation we have recently developed synthetic LXA mimetics (sLXms) including a dimethyl-imidazole-containing FPR2/ALX agonist designated AT-01-KG. Here, we have investigated the effect of treatment with AT-01-KG in established models of articular inflammation. In a model of gout, mice were injected with MSU crystals and treated with AT-01-KG at the peak of inflammatory response. The treatment decreased the number of neutrophils in the knee exudate, an effect which was accompanied by low levels of myeloperoxidase, CXCL1 and IL-1β in periarticular tissue. AT-01-KG treatment led to reduced tissue damage and hypernociception. The effects of AT-01-KG on neutrophil accumulation were not observed in MSU treated FPR2/3mice. Importantly, AT-01-KG induced resolution of articular inflammation by increasing neutrophil apoptosis and subsequent efficient efferocytosis. In a model of antigen-induced arthritis, AT-01-KG treatment also attenuated inflammatory responses. These data suggest that AT-01-KG may be a potential new therapy for neutrophilic inflammation of the joints.
炎症消退是一个动态过程，其特征是合成促炎消退介质，包括脂质脂氧素 A4（LXA）。LXA 作用于 N-甲酰肽受体 2（FPR2/ALX）以介导抗炎和促消退作用。为了利用炎症背景下内源性 LXA 的治疗潜力，我们最近开发了合成 LXA 模拟物（sLXms），包括一种含二甲基咪唑的 FPR2/ALX 激动剂，命名为 AT-01-KG。在这里，我们研究了在关节炎症的既定模型中用 AT-01-KG 治疗的效果。在痛风模型中，将 MSU 晶体注射到小鼠体内，并在炎症反应高峰期用 AT-01-KG 治疗。该治疗减少了膝关节渗出液中的中性粒细胞数量，这一作用伴随着周围组织中低水平的髓过氧化物酶、CXCL1 和 IL-1β。AT-01-KG 治疗导致组织损伤和痛觉过敏减轻。在 MSU 处理的 FPR2/3 小鼠中，未观察到 AT-01-KG 对中性粒细胞积累的影响。重要的是，AT-01-KG 通过增加中性粒细胞凋亡和随后有效的吞噬作用来诱导关节炎症消退。在抗原诱导关节炎模型中，AT-01-KG 治疗也减轻了炎症反应。这些数据表明，AT-01-KG 可能是一种治疗关节中性粒细胞炎症的新潜在疗法。
