Tian Yuan, Chen Jiongcheng, Huang Wenshu, Ren Qian, Feng Junxia, Liao Jinlin, Fu Haiyan, Zhou Lili, Liu Youhua
State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Nephrology, Jingzhou Hospital Affiliated to Yangze University, Jingzhou, China.
Int J Biol Sci. 2024 Apr 8;20(6):2310-2322. doi: 10.7150/ijbs.94166. eCollection 2024.
Wnt/β-catenin signaling plays a pivotal role in the pathogenesis of chronic kidney diseases (CKD), which is associated with macrophage activation and polarization. However, the relative contribution of macrophage-derived Wnts in the evolution of CKD is poorly understood. Here we demonstrate a critical role of Wnts secreted by macrophages in regulating renal inflammation and fibrosis after various injuries. In mouse model of kidney fibrosis induced by unilateral ureteral obstruction (UUO), macrophages were activated and polarized to M1 and M2 subtypes, which coincided with the activation of Wnt/β-catenin signaling. , multiple Wnts were induced in primary cultured bone marrow-derived macrophages (BMDMs) after polarization. Conversely, Wnt proteins also stimulated the activation and polarization of BMDMs to M1 and M2 subtype. Blockade of Wnt secretion from macrophages in mice with myeloid-specific ablation of Wntless (Wls), a cargo receptor that is obligatory for Wnt trafficking and secretion, blunted macrophage infiltration and activation and inhibited the expression of inflammatory cytokines. Inhibition of Wnt secretion by macrophages also abolished β-catenin activation in tubular epithelium, repressed myofibroblast activation and reduced kidney fibrosis after either obstructive or ischemic injury. Furthermore, conditioned medium from Wls-deficient BMDMs exhibited less potency to stimulate fibroblast proliferation and activation, compared to the controls. These results underscore an indispensable role of macrophage-derived Wnts in promoting renal inflammation, fibroblasts activation and kidney fibrosis.
Wnt/β-连环蛋白信号通路在慢性肾脏病（CKD）的发病机制中起关键作用，这与巨噬细胞的激活和极化相关。然而，巨噬细胞源性Wnts在CKD进展中的相对作用尚不清楚。在此，我们证明了巨噬细胞分泌的Wnts在各种损伤后调节肾脏炎症和纤维化中起关键作用。在单侧输尿管梗阻（UUO）诱导的肾纤维化小鼠模型中，巨噬细胞被激活并极化为M1和M2亚型，这与Wnt/β-连环蛋白信号通路的激活相一致。极化后，原代培养的骨髓来源巨噬细胞（BMDM）中多种Wnts被诱导。相反，Wnt蛋白也刺激BMDM激活并极化为M1和M2亚型。在具有Wntless（Wls）髓系特异性缺失的小鼠中，Wls是Wnt运输和分泌所必需的货物受体，阻断巨噬细胞分泌Wnt，可减弱巨噬细胞浸润和激活，并抑制炎性细胞因子的表达。巨噬细胞分泌Wnt的抑制也消除了肾小管上皮细胞中的β-连环蛋白激活，抑制了肌成纤维细胞激活，并减少了梗阻性或缺血性损伤后的肾纤维化。此外，与对照相比，来自Wls缺陷型BMDM的条件培养基刺激成纤维细胞增殖和激活的能力较弱。这些结果强调了巨噬细胞源性Wnts在促进肾脏炎症、成纤维细胞激活和肾纤维化中的不可或缺的作用。
