Eissa Nour, Elgazzar Omar, Hussein Hayam, Hendy Geoffrey N, Bernstein Charles N, Ghia Jean-Eric
Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0T5, Canada.
Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P4, Canada.
Biomedicines. 2021 Feb 1;9(2):134. doi: 10.3390/biomedicines9020134.
Ulcerative colitis (UC) is characterized by modifying alternatively activated macrophages (AAM) and epithelial homeostasis. Chromogranin-A (CHGA), released by enterochromaffin cells, is elevated in UC and is implicated in inflammation progression. CHGA can be cleaved into several derived peptides, including pancreastatin (PST), which is involved in proinflammatory mechanisms. Previously, we showed that the deletion of decreased the onset and severity of colitis correlated with an increase in AAM and epithelial cells' functions. Here, we investigated PST activity in colonic biopsies of participants with active UC and investigated PST treatment in dextran sulfate sodium (DSS)-induced colitis using mice, macrophages, and a human colonic epithelial cells line. We found that the colonic protein expression of PST correlated negatively with mRNA expression of AAM markers and tight junction (TJ) proteins and positively with mRNA expression of interleukin (IL)-8, IL18, and collagen in human. In a preclinical setting, intra-rectal administration of PST aggravated DSS-induced colitis by decreasing AAM's functions, enhancing colonic collagen deposition and disrupting epithelial homeostasis in and mice. This effect was associated with a significant reduction in AAM markers, increased colonic IL-18 release, and decreased TJ proteins' gene expression. In vitro, PST reduced and AAM polarization and decreased anti-inflammatory mediators' production. Conditioned medium harvested from PST-treated and AAM reduced Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins and increased oxidative stress-induced apoptosis and proinflammatory cytokines release. In conclusion, PST is a CHGA proinflammatory peptide that enhances the severity of colitis and the inflammatory process via decreasing AAM functions and disrupting epithelial homeostasis.
溃疡性结肠炎（UC）的特征是交替活化巨噬细胞（AAM）的改变和上皮内稳态。嗜铬粒蛋白A（CHGA）由肠嗜铬细胞释放，在UC中升高，并与炎症进展有关。CHGA可被切割成几种衍生肽，包括胰抑素（PST），其参与促炎机制。此前，我们发现[此处缺失信息]的缺失降低了结肠炎的发病和严重程度，这与AAM和上皮细胞功能的增加相关。在此，我们研究了活动性UC参与者结肠活检中PST的活性，并使用[此处缺失信息]小鼠、巨噬细胞和人结肠上皮细胞系研究了PST对葡聚糖硫酸钠（DSS）诱导的结肠炎的治疗作用。我们发现，人结肠中PST的蛋白表达与AAM标志物和紧密连接（TJ）蛋白的mRNA表达呈负相关，与白细胞介素（IL）-8、IL-18和胶原蛋白的mRNA表达呈正相关。在临床前研究中，直肠内给予PST通过降低AAM功能、增强结肠胶原蛋白沉积以及破坏[此处缺失信息]和[此处缺失信息]小鼠的上皮内稳态，加重了DSS诱导的结肠炎。这种效应与AAM标志物的显著减少、结肠IL-18释放的增加以及TJ蛋白基因表达的降低有关。在体外，PST减少了[此处缺失信息]和[此处缺失信息]AAM的极化，并降低了抗炎介质的产生。从PST处理的[此处缺失信息]和[此处缺失信息]AAM收集的条件培养基降低了Caco-2细胞的迁移、活力、增殖以及TJ蛋白的mRNA水平，并增加了氧化应激诱导的细胞凋亡和促炎细胞因子的释放。总之，PST是一种CHGA促炎肽，它通过降低AAM功能和破坏上皮内稳态来加重结肠炎的严重程度和炎症过程。
