Objective To study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing. Design We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin. Results Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. Conclusion In addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.

中文翻译：

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非经典单核细胞通过α4β7整合素归巢至肠道介导巨噬细胞依赖性肠道伤口愈合

目的 研究 α4β7 整合素在单核细胞归巢中的作用，并探讨治疗性 α4β7 抑制对肠道伤口愈合的生物学影响。设计 我们使用流式细胞术和免疫组织化学研究了 IBD 患者和对照组外周血中单核细胞亚群和肠道巨噬细胞亚群上的归巢标记物的表达。整合素功能通过动态粘附测定和体内肠道归巢测定得到解决。在缺乏或耗尽 α4β7 整联蛋白的小鼠中研究了体内伤口愈合。结果经典和非经典单核细胞在归巢标志物表达方面明显存在二分法，包括α4β7整合素在人和小鼠非经典单核细胞上的相关表达，但在经典单核细胞上没有。单核细胞表达的 α4β7 整联蛋白对于动态粘附到粘膜血管地址蛋白细胞粘附分子 1 和体内肠道归巢具有重要的功能。α4β7 依赖性肠道归巢受损与伤口愈合的减少（效应量约 20%）和延迟以及伤口愈合巨噬细胞的病灶周围存在受到抑制有关。在接受维多珠单抗临床治疗的 IBD 患者中，外周血中的非经典单核细胞增加。结论 除了报道的对淋巴细胞的影响外，IBD 中的抗 α4β7 治疗还针对非经典单核细胞。这种单核细胞的肠道归巢受损可能导致伤口愈合巨噬细胞减少，并可能解释维多珠单抗治疗患者术后并发症发生率增加的原因，这在一些研究中已经观察到。