Formyl peptide receptor 1 signalling promotes experimental colitis in mice
Formyl peptide receptor 1 signalling promotes experimental colitis in mice
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DOI：
10.1016/j.phrs.2019.01.041
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发表时间：
2019-03-01
影响因子：
9.3
通讯作者：
Cuzzocrea, Salvatore
中科院分区：
文献类型：
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作者：
Di Paola, Rosanna;Fusco, Roberta;Cuzzocrea, Salvatore
炎症性肠病的特点是免疫细胞与组织细胞之间复杂的相互作用，并且这种相互作用可能会失调。甲酰肽受体 1 (Fpr1) 由免疫细胞和基质细胞（包括上皮细胞）表达。我们与 C57BL/6 遗传背景动物相比，评估了 C57BL/6 遗传背景的 Fpr1 KO 小鼠中 DNBS 诱导的结肠炎的病理生理学发展。我们评估了患病者的宏观和组织学标记，以及免疫组织化学和分子变化。 DNBS 处理的 Fpr1 KO 小鼠表现出：i) 体重减轻减少，ii) 结肠损伤程度降低，以及 iii) MPO 活性增加。分子分析表明，在 Fpr1 缺失的情况下，NF-κ B 易位入核、细胞因子水平、FOXP3 和 GATA3、CD4、CD8 和 CD45 表达降低，以及 TGF-β 信号传导失调。此外，与相应的WT小鼠相比，注射DNBS的Fpr1 KO小鼠的结肠显示出较低程度的Bax表达和较高程度的Bcl-2表达。最后，对 DNBS 滴注后微循环的活体显微镜检查显示，Fpr1 KO 小鼠中由 P-选择素和 ICAM-1 介导的中性粒细胞内皮细胞滚动和粘附程度较低。研究中所有主要结果的P值、证据的统计显着性均小于0.05。我们提供了小鼠 Fpr1 在实验性结肠炎中重要致病作用的证据，这是通过调节免疫细胞募集以及调节局部细胞激活和存活来实现的结果。
Inflammatory bowel disease is characterised by intricate immune cell interactions with tissue cells and such cross-talks can become deregulated. The formyl peptide receptor 1 (Fpr1) is expressed by both immune and stromal cells including epithelial cells. We evaluated the development of the physiopathology of the DNBS induced colitis in Fpr1 KO mice on the C57BL/6 genetic background compared to C57BL/6 genetic background animals. We have assessed both macroscopic and histological markers of the diseased, together with the immunohistochemical and molecular changes. DNBS-treated Fpr1 KO mice showed a i) reduction in weight loss, ii) lower extent of colon injury and iii) an increase in MPO activity. Molecular analyses indicated that in absence of Fpr1 there was reduced NF-kappa B translocation into the nucleus, cytokines levels, FOXP3 and GATA3, CD4, CD8 and CD45 expression as well as a dysregulation of TGF-beta signalling. In addition, the colon of DNBS-injected Fpr1 KO mice displayed a lower degree of expression of Bax and higher expression of Bcl-2 compared correspondent WT mice. Finally, intravital microscopy investigation of the microcirculation post-DNBS instillation revealed a lower degree of neutrophil-endothelial cell rolling and adhesion - mediated by P-selectin and ICAM-1 - in Fpr1 KO mice. All the main outcome in the study have a P-value, statistical significance of evidence, less than 0.05. We provide evidence for an important pathogenic role of mouse Fpr1 in experimental colitis, an outcome effected through modulation of immune cell recruitment together with a modulation of local cellular activation and survival.