炎症性肠病 (IBD) 的最新且最有前途的治疗策略采用了针对参与免疫炎症过程主要步骤的单一效应成分的生物制剂，例如肿瘤坏死因子、白细胞介素或整合素。然而，这些分子尚未达到功效和安全性方面的预期，导致难治性或复发性患者比例很高。因此，迫切需要新的治疗方案。补体抑制剂 C4b 结合蛋白的次要异构体 C4BP(β-) 已被证明能够赋予炎症骨髓细胞强大的抗炎和免疫调节表型。在这里，我们表明，C4BP（β-）介导的免疫调节可以显着减弱葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的组织病理学特征并保持肠上皮完整性。 C4BP(β-) 下调炎症转录本，特别是与中性粒细胞活性相关的转录本，减轻循环炎症效应细胞因子和趋化因子（如 CXCL13），这是产生异位淋巴结构的关键，并且总体而言，防止结肠炎小鼠结肠中的炎症免疫细胞浸润。 PRP6-HO7 是一种仅具有免疫调节活性的重组缩减类似物，取得了与 C4BP(β-) 相似的结果，表明治疗效果不是由于补体抑制活性。此外，C4BP(β-) 和 PRP6-HO7 均显着降低了溃疡性结肠炎和克罗恩病患者骨髓细胞中固有的和 TLR 诱导的炎症标志物，且疗效相当，无论他们接受何种药物治疗。因此，PRP6-HO7 的多效抗炎和免疫调节活性，能够从复杂的炎症肠道环境中“重新编程”骨髓细胞并恢复免疫稳态，可能构成 IBD 的一种有前景的治疗选择。版权所有 © 2023。由 Elsevier 出版有限公司

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(β-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(β-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(β-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to "reprogram" myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.Copyright © 2023. Published by Elsevier Ltd.