Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Mucosal Immunol. 2016 Jul;9(4):986-98. doi: 10.1038/mi.2015.123. Epub 2015 Nov 25.
The complete repair of the mucosa constitutes a key goal in inflammatory bowel disease (IBD) treatment. The Wnt signaling pathway mediates mucosal repair and M2 macrophages that coordinate efficient healing have been related to Wnt ligand expression. Signal transducer and activator of transcription 6 (STAT6) mediates M2 polarization in vitro and we hypothesize that a STAT6-dependent macrophage phenotype mediates mucosal repair in acute murine colitis by activating the Wnt signaling pathway. Our results reveal an impaired mucosal expression of M2 macrophage-associated genes and delayed wound healing in STAT6(-/-) mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). These mice also exhibited decreased mucosal expression of Wnt2b, Wnt7b, and Wnt10a, diminished protein levels of nuclear β-catenin that is mainly located in crypts adjacent to damage, and reduced mRNA expression of two Wnt/β-catenin target molecules Lgr5 and c-Myc when compared with wild-type (WT) mice. Murine peritoneal macrophages treated with interleukin-4 (IL-4) and polarized toward an M2a phenotype overexpressed Wnt2b, Wnt7b, and Wnt10a in a STAT6-dependent manner. Administration of a Wnt agonist as well as transfer of properly polarized M2a macrophages to STAT6(-/-) mice activated the Wnt signaling pathway in the damaged mucosa and accelerated wound healing. Our results demonstrate that a STAT6-dependent macrophage phenotype promotes mucosal repair in TNBS-treated mice through activation of the Wnt signaling pathway.
黏膜的完全修复是炎症性肠病（IBD）治疗的关键目标。Wnt 信号通路介导黏膜修复，与 Wnt 配体表达相关的 M2 巨噬细胞协调有效的愈合。信号转导和转录激活因子 6（STAT6）在体外介导 M2 极化，我们假设 STAT6 依赖性巨噬细胞表型通过激活 Wnt 信号通路介导急性小鼠结肠炎中的黏膜修复。我们的研究结果揭示了 STAT6（-/-）小鼠在接受 2,4,6-三硝基苯磺酸（TNBS）治疗时，黏膜中 M2 巨噬细胞相关基因的表达受损，伤口愈合延迟。与野生型（WT）小鼠相比，这些小鼠的黏膜中 Wnt2b、Wnt7b 和 Wnt10a 的表达减少，核 β-连环蛋白的蛋白水平降低，β-连环蛋白主要位于损伤附近的隐窝中，并且 Wnt/β-连环蛋白靶分子 Lgr5 和 c-Myc 的 mRNA 表达减少。用白细胞介素 4（IL-4）处理的小鼠腹腔巨噬细胞并向 M2a 表型极化，以 STAT6 依赖性方式过表达 Wnt2b、Wnt7b 和 Wnt10a。Wnt 激动剂的给药以及适当极化的 M2a 巨噬细胞向 STAT6（-/-）小鼠的转移激活了受损黏膜中的 Wnt 信号通路并加速了伤口愈合。我们的研究结果表明，STAT6 依赖性巨噬细胞表型通过激活 Wnt 信号通路促进 TNBS 处理的小鼠中的黏膜修复。
