Programa de Pós-Graduação em Biologia Celular, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
J Leukoc Biol. 2012 Aug;92(2):249-58. doi: 10.1189/jlb.0112008. Epub 2012 Apr 9.
This study aimed at assessing whether AnxA1, a downstream mediator for the anti-inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 μg, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-κB. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis.
本研究旨在评估抗炎作用的 GC 的下游介质 AnxA1 是否会影响组织渗出液中免疫细胞的命运，方法是使用 LPS 诱导的 BALB/c 小鼠胸膜炎。在 LPS 后 48-72 小时，自然消退过程中渗出液中的 AnxA1 蛋白表达增加，GC 处理增强了这种作用，并伴有胸膜渗出液中凋亡中性粒细胞的明显存在。使用中性化抗体或 FPR/ALXRs 的非特异性拮抗剂来确定 AnxA1 的功能相关性：两种治疗均抑制炎症的自发和 GC 诱导消退。注射 Ac2-26（100μg，在 LPS 反应后 4 小时给予），一种有效的 AnxA1 活性 N 端肽，促进了主动消退，并增加了中性粒细胞凋亡的程度。这种作用被广谱半胱天冬酶抑制剂 zVAD-fmk 所阻止。从机制上讲，中性粒细胞炎症的消退与细胞凋亡有关，伴随着 Bax 和 caspase-3 的激活以及抑制生存途径 Mcl-1、ERK1/2 和 NF-κB。这些使用急性炎症动态模型的新体内数据提供了证据，表明 AnxA1 是天然和 GC 诱导炎症消退的介质，对中性粒细胞凋亡有深远影响。
