Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
PLoS One. 2013 Apr 26;8(4):e62257. doi: 10.1371/journal.pone.0062257. Print 2013.
Inflammatory bowel diseases are a critical public health issue, and as treatment options remain limited, there is a need to unravel the underlying pathomechanisms in order to identify new therapeutic targets. Complement activation was found in patients suffering from inflammatory bowel disease, and the complement anaphylatoxin C5a and its receptor C5aR have been implicated in disease pathogenesis in animal models of bowel inflammation. To further characterize complement-related pathomechanisms in inflammatory bowel disease, we have investigated the role of the anaphylatoxin C3a receptor in acute dextran sulfate sodium-induced colitis in mice. For this, colitis was induced in C3a receptor-deficient BALB/c and C57BL/6 mice, and disease severity was evaluated by clinical and histological examination, and by measuring the mRNA expression or protein levels of inflammatory mediators in the tissue. C3a receptor deficiency was partially protective in BALB/c mice, which had significantly reduced weight loss, clinical and histological scores, colon shortening, and CXCL-1/KC mRNA, myeloperoxidase and interleukin-6 tissue levels compared to the corresponding wild type mice. In C57BL/6 mice the differences between wild type and C3a receptor-deficient animals were much smaller and reached no significance. Our data demonstrate that the contribution of C3a receptor to disease pathogenesis and severity of dextran sulfate sodium-induced colitis in mice depends on the genetic background. Further studies will be required to clarify whether targeting of C3a receptor, possibly in combination with C5a receptor, might be considered as a therapeutic strategy for inflammatory bowel disease.
炎症性肠病是一个严重的公共卫生问题，由于治疗选择仍然有限，因此需要揭示潜在的发病机制，以确定新的治疗靶点。在患有炎症性肠病的患者中发现了补体激活，并且补体过敏毒素 C5a 及其受体 C5aR 已被牵连到动物模型中的肠道炎症发病机制中。为了进一步描述炎症性肠病中的补体相关发病机制，我们研究了过敏毒素 C3a 受体在急性葡聚糖硫酸钠诱导的小鼠结肠炎中的作用。为此，在 C3a 受体缺陷型 BALB/c 和 C57BL/6 小鼠中诱导结肠炎，并通过临床和组织学检查以及测量组织中炎症介质的 mRNA 表达或蛋白水平来评估疾病严重程度。C3a 受体缺陷在 BALB/c 小鼠中具有部分保护作用，与相应的野生型小鼠相比，其体重减轻、临床和组织学评分、结肠缩短以及 CXCL-1/KC mRNA、髓过氧化物酶和白细胞介素-6 组织水平均显著降低。在 C57BL/6 小鼠中，野生型和 C3a 受体缺陷型动物之间的差异要小得多，并且没有达到显著性。我们的数据表明，C3a 受体对疾病发病机制和葡聚糖硫酸钠诱导的小鼠结肠炎严重程度的贡献取决于遗传背景。需要进一步的研究来阐明是否可以考虑靶向 C3a 受体（可能与 C5a 受体联合）作为炎症性肠病的治疗策略。
