Glial cell line-derived neurotrophic factor (GDNF) has been reported to protect mice from intestinal inflammation, but its anti-inflammatory mechanisms are poorly understood. Here we found that there was a downregulation in intestinal expression of GDNF accompanied by an increase of M1 macrophages in dextran sulfate sodium (DSS)-induced colitis in mice. GDNF treatment could facilitate the macrophages polarization towards the M2-like phenotype in DSS-treated mice and LPS-stimulated RAW264.7 cells, and reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines. Mechanistically, the activation of PI3K/AKT pathway might contribute to the regulation of GDNF on macrophage phenotypes and inflammatory response. Moreover, the administration of GDNF significantly ameliorated colitis in DSS-treated mice, but this benefit of GDNF was diminished by macrophage depletion. Therefore, we propose a new mechanism whereby GDNF suppresses DSS-induced colitis in mice via a macrophage-mediated pathway.

据报道，胶质细胞源性神经营养因子 (GDNF) 可保护小鼠免受肠道炎症，但其抗炎机制知之甚少。在这里，我们发现 GDNF 的肠道表达下调，伴随着葡聚糖硫酸钠 (DSS) 诱导的小鼠结肠炎中 M1 巨噬细胞的增加。GDNF 治疗可促进 DSS 处理的小鼠和 LPS 刺激的 RAW264.7 细胞中巨噬细胞向 M2 样表型极化，并减少促炎细胞因子并增加抗炎细胞因子。从机制上讲，PI3K/AKT 通路的激活可能有助于 GDNF 对巨噬细胞表型和炎症反应的调节。此外，给予 GDNF 显着改善了 DSS 治疗小鼠的结肠炎，但 GDNF 的这种好处因巨噬细胞耗竭而减弱。因此，我们提出了一种新机制，即 GDNF 通过巨噬细胞介导的途径抑制 DSS 诱导的小鼠结肠炎。