Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis
Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis
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DOI：
10.3389/fimmu.2020.00093
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发表时间：
2020-01-31
影响因子：
7.3
通讯作者：
Wehkamp, Jan
中科院分区：
文献类型：
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作者：
Koeninger, Louis;Armbruster, Nicole S.;Wehkamp, Jan
防御素代表先天免疫系统的组成部分，用于抵御潜在的病原体并保护肠道屏障免受微生物侵入。除了它们的抗微生物活性之外，一般的防御素，特别是人β-防御素2（hBD 2），也表现出免疫调节能力。在这份报告中，我们评估了全身给予重组hBD 2改善三种不同的炎症性肠病动物模型中肠道炎症的治疗效果;即，化学诱导的粘膜损伤（DSS）、粘膜耐受性丧失（TNBS）和T细胞转移到免疫缺陷受体小鼠中。在所有测试的模型中证实了治疗功效，其中全身施用hBD 2减轻炎症，改善疾病活动指数，并与抗TNF-α和类固醇同等地阻碍结肠炎诱导的体重减轻。用rhBD 2处理脂多糖（LPS）活化的人外周血单核细胞证实了循环隔室中的免疫调节能力。随后的分析显示树突状细胞（DC）是主要的靶群体。LPS诱导的炎症抑制依赖于趋化因子受体2（CCR 2）的表达。在机制上，hBD 2与其DC靶细胞上的CCR 2接合以减少NF-κ B，并增加CREB磷酸化，从而抑制炎症。据我们所知，这是第一个研究显示在实验性疾病中全身施用防御素的体内功效。
Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human beta-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-alpha and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-kappa B, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing in vivo efficacy of a systemically administered defensin in experimental disease.