CD44 is a transmembrane molecule appearing in numerous isoforms generated by insertions of alternatively spliced variant exons (CD44v) and having various binding partners. CD44v7 on T cells was proposed to promote colitis by preventing T-cell apoptosis. Here we demonstrate that Cd44v7-deficient T cells - like Cd44 wild-type (Cd44^WT) T cells - provoked disease in two different colitis models: the model induced by CD4⁺CD45RB^high T-cell transfer into Rag2-deficient mice and a new model based on ovalbumin (OVA)-specific T-cell transfer into Rag-sufficient, OVA-challenged mice. In contrast, CD44v7 absence on macrophages in recipient mice prevented colitis. Prevention was associated with the downregulation of signal transducer and activator of transcription 3 (STAT3)-activating and Foxp3-counteracting interleukin-6 (IL-6), lower numbers of phospho-STAT3-containing lymphocytes, and higher Foxp3⁺ T-cell counts in the colon. Consequently, the protected colons showed lower IL-12, IL-1β expression, and decreased interferon-γ levels. Importantly, stimulation of T cells by Cd44v7-deficient macrophages induced upregulation of Foxp3 in vitro, while cotransfer of Cd44^WT macrophages into Cd44v7-deficient mice reduced Foxp3⁺ T-cell counts and caused colitis. Accordingly, the CD44v7 ligand osteopontin, whose levels were elevated in Crohn's disease, specifically induced IL-6 in human monocytes, a cytokine also increased in these patients. We suggest macrophage-specific targeting of the CD44v7 pathway as a novel therapeutic option for Crohn's disease.

中文翻译：

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巨噬细胞中 CD44 特异性选择性剪接外显子的缺失可预防结肠炎。

CD44 是一种跨膜分子，出现在通过插入可变剪接变异外显子 (CD44v) 并具有各种结合伙伴而产生的许多亚型中。T 细胞上的 CD44v7 被提议通过阻止 T 细胞凋亡来促进结肠炎。在这里，我们证明 Cd44v7 缺陷型 T 细胞 - 如 Cd44 野生型 (Cd44 ^{WT ) T 细胞 - 在两种不同的结肠炎模型中引发疾病：CD4 +} CD45RB ^high诱导的模型T 细胞转移到 Rag2 缺陷小鼠和基于卵清蛋白 (OVA) 特异性 T 细胞转移到 Rag 充足、OVA 攻击小鼠的新模型。相比之下，受体小鼠巨噬细胞上 CD44v7 的缺失可预防结肠炎。预防与信号转导和转录激活因子 3 (STAT3) 激活和 Foxp3 反作用白细胞介素 6 (IL-6) 的下调、含磷酸化 STAT3 的淋巴细胞数量减少以及 Foxp3 ⁺ T 细胞计数增加有关在结肠中。因此，受保护的结肠显示出较低的 IL-12、IL-1β 表达和较低的干扰素-γ 水平。重要的是，Cd44v7 缺陷型巨噬细胞对 T 细胞的刺激在体外诱导 Foxp3 的上调，而 Cd44 ^WT巨噬细胞共转移到 Cd44v7 缺陷型小鼠中会减少 Foxp3⁺ T 细胞计数并引起结肠炎。因此，在克罗恩病中水平升高的 CD44v7 配体骨桥蛋白在人单核细胞中特异性诱导 IL-6，一种细胞因子在这些患者中也增加。我们建议将 CD44v7 通路的巨噬细胞特异性靶向作为克罗恩病的一种新型治疗选择。