Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis
Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis
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DOI：
10.1038/mi.2014.21
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发表时间：
2014-11-01
影响因子：
8
通讯作者：
Singh, A. B.
中科院分区：
文献类型：
--
作者：
Ahmad, R.;Chaturvedi, R.;Singh, A. B.
claudin-2是一种紧密连接蛋白，在炎症性肠病（IBD）期间表达高度上调，并且由于其与上皮通透性相关，已被认为可促进炎症。值得注意的是，claudin-2也参与肠上皮细胞增殖的调节。然而，claudin-2在调节结肠内稳态中的确切作用尚不清楚。在这里，我们证明，使用绒毛蛋白- claudin-2转基因小鼠，增加结肠claudin-2表达增加粘膜通透性以及结肠和隐窝的长度。最值得注意的是，尽管存在结肠渗漏，但Cl-2TG小鼠对实验性结肠炎有明显的保护作用。重要的是，claudin-2的表达增加了结肠炎诱导的结肠炎细胞增殖，并以PI-3Kinase/ bcl -2依赖的方式对结肠炎诱导的结肠炎细胞死亡提供保护。然而，Cl-2TG小鼠也表现出明显抑制结肠炎诱导的免疫激活和相关信号的增加，表明免疫耐受。因此，初生Cl-2TG小鼠的结肠中调节性（CD4+ Foxp3+） T细胞的数量明显高于WT幼崽。此外，从Cl-2TG小鼠结肠中分离的巨噬细胞表现出免疫能量。重要的是，与WT幼崽相比，这些免疫抑制变化与Cl-2TG小鼠结肠上皮细胞合成免疫调节细胞因子TGF-β增加有关。综上所述，我们的研究结果揭示了cladin -2通过调节上皮通透性、炎症和增殖在肠道内稳态中发挥重要而复杂的作用，并提出了新的治疗机会。
Expression of claudin-2, a tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Notably, claudin-2 has also been implicated in the regulation of intestinal epithelial proliferation. However, precise role of claudin-2 in regulating colonic homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic mice, that increased colonic claudin-2 expression augments mucosal permeability as well as colon and crypt length. Most notably, despite leaky colon, Cl-2TG mice were significantly protected against experimental colitis. Importantly, claudin-2 expression increased colonocyte proliferation and provided protection against colitis-induced colonocyte death in a PI-3Kinase/Bcl-2-dependent manner. However, Cl-2TG mice also demonstrated marked suppression of colitis-induced increases in immune activation and associated signaling, suggesting immune tolerance. Accordingly, colons from naive Cl-2TG mice harbored significantly increased numbers of regulatory (CD4+ Foxp3+) T cells than WT littermates. Furthermore, macrophages isolated from Cl-2TG mouse colon exhibited immune anergy. Importantly, these immunosuppressive changes were associated with increased synthesis of the immunoregulatory cytokine TGF-β by colonic epithelial cells in Cl-2TG mice compared with WT littermates. Taken together, our findings reveal a critical albeit complex role of claudin-2 in intestinal homeostasis by regulating epithelial permeability, inflammation and proliferation and suggest novel therapeutic opportunities.