Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada.
PLoS One. 2012;7(6):e39244. doi: 10.1371/journal.pone.0039244. Epub 2012 Jun 18.
One of the characteristics of an active episode of ulcerative colitis (UC) is the intense mucosal infiltration of leukocytes. The pro-resolution mediators Annexin-A1 (AnxA1) and lipoxin A(4) (LXA(4)) exert counter-regulatory effects on leukocyte recruitment, however to date, the dual/cumulative effects of these formyl peptide receptor-2 (FPR2/ALX) agonists in the context of human intestinal diseases are unclear. To define the contribution of these mediators, we measured their expression in biopsies from individuals with UC.
Colonic mucosal biopsies were collected from two broad patient groups: healthy volunteers without ('Ctrl' n = 20) or with a prior history of UC ('hx of UC' n = 5); individuals with UC experiencing active disease ('active' n = 8), or in medically-induced remission ('remission' n = 16). We assessed the mucosal expression of LXA(4), AnxA1, and the FPR2/ALX receptor in each patient group using a combination of fluorescence microscopy, biochemical and molecular analyses.
Mucosal expression of LXA(4) was elevated exclusively in biopsies from individuals in remission (3-fold, P<0.05 vs. Ctrl). Moreover, in this same group we observed an upregulation of AnxA1 protein expression (2.5-fold increase vs. Ctrl, P<.01), concurrent with an increased level of macrophage infiltration, and an elevation in FPR2/ALX mRNA (7-fold increase vs. Ctrl, P<.05). Importantly, AnxA1 expression was not limited to cells infiltrating the lamina propria but was also detected in epithelial cells lining the intestinal crypts.
Our results demonstrate a specific up-regulation of this pro-resolution circuit in individuals in remission from UC, and suggest a significant role for LXA(4) and AnxA1 in promoting mucosal homeostasis.
溃疡性结肠炎（UC）活动期的一个特征是白细胞强烈浸润黏膜。促解决介质膜联蛋白 A1（AnxA1）和脂氧素 A4（LXA4）对白细胞募集发挥反向调节作用，然而迄今为止，这些形式肽受体 2（FPR2/ALX）激动剂在人类肠道疾病中的双重/累积作用尚不清楚。为了确定这些介质的贡献，我们测量了它们在患有 UC 的个体活检中的表达。
从两组广泛的患者中收集结肠黏膜活检：无（Ctrl n = 20）或有溃疡性结肠炎既往史（UC hx n = 5）的健康志愿者；患有 UC 且处于活动期（active n = 8）或经医学诱导缓解期（remission n = 16）的个体。我们使用荧光显微镜、生化和分子分析相结合的方法，评估了每位患者组中 LXA4、AnxA1 和 FPR2/ALX 受体的黏膜表达。
仅在缓解期个体的活检中观察到 LXA4 的黏膜表达升高（增加 3 倍，P<0.05 与 Ctrl 相比）。此外，在同一组中，我们观察到 AnxA1 蛋白表达上调（与 Ctrl 相比增加 2.5 倍，P<.01），同时巨噬细胞浸润增加，FPR2/ALX mRNA 水平升高（与 Ctrl 相比增加 7 倍，P<.05）。重要的是，AnxA1 的表达不仅限于浸润固有层的细胞，也在肠道隐窝衬里的上皮细胞中检测到。
我们的结果表明，在 UC 缓解期个体中，这种促解决回路特异性上调，并表明 LXA4 和 AnxA1 在促进黏膜稳态方面具有重要作用。
