Wnt Coreceptor Lrp5 Is a Driver of Idiopathic Pulmonary Fibrosis
Wnt Coreceptor Lrp5 Is a Driver of Idiopathic Pulmonary Fibrosis
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DOI：
10.1164/rccm.201401-0079oc
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发表时间：
2014-07-15
影响因子：
24.7
通讯作者：
Gottardi, Cara J.
中科院分区：
文献类型：
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作者：
Lam, Anna P.;Herazo-Maya, Jose D.;Gottardi, Cara J.
基本原理：Wnt/β-catenin信号转导与肺纤维化有关，但其发生机制以及Wnt通路组分的表达变化是否能预测疾病进展尚不清楚。目的：确定Wnt辅助受体Lrp 5是否能驱动小鼠肺纤维化，并预测人类疾病的严重程度。我们在博莱霉素或编码转化生长因子活性形式的腺病毒诱导的肺纤维化模型中，检测了Wnt辅助受体Lrp 5缺失导致的Wnt信号传导受损的小鼠（TGF）-β。我们还分析了特发性肺纤维化（IPF）患者外周血单个核细胞（PBMC）的基因表达，测量和主要结果：在IPF患者中，外周血单个核细胞的分析显示，阳性调节因子Lrp 5和6的升高与疾病进展独立相关。在另一个IPF患者队列中，LRP 5也与疾病严重程度相关。Lrp 5基因敲除的小鼠被保护免于博来霉素诱导的肺纤维化，该作用通过β-连环蛋白应答性转录的小分子抑制剂直接抑制β-连环蛋白信号传导而表型化。将Lrp 5缺失的骨髓细胞移植到野生型小鼠中并不限制纤维化。相反，Lrp 5丢失与肺泡2型细胞和白细胞产生TGF-β减少有关。与Lrp 5在TGF-β激活中的作用一致，Lrp 5缺失小鼠不受TGF-β诱导的肺纤维化的保护。结论：我们表明Wnt辅助受体Lrp 5是小鼠肺纤维化的遗传驱动因子，也是人类IPF疾病进展和严重程度的标志物。TGF-β信号传导可以覆盖Lrp 5损失的证据对肺纤维化患者的选择和Wnt通路抑制剂的时机有影响。
Rationale: Wnt/beta-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown.Objectives: To determine whether the Wnt coreceptor Lrp5 drives pulmonary fibrosis in mice and is predictive of disease severity in humans.Methods: We examined mice with impaired Wnt signaling caused by loss of the Wnt coreceptor Lrp5 in models of lung fibrosis induced by bleomycin or an adenovirus encoding an active form of transforming growth factor (TGF)-beta. We also analyzed gene expression in peripheral blood mononuclear cells (PBMC) from patients with idiopathic pulmonary fibrosis (IPF).Measurements and Main Results: In patients with IPF, analysis of peripheral blood mononuclear cells revealed that elevation of positive regulators, Lrp5 and 6, was independently associated with disease progression. LRP5 was also associated with disease severity at presentation in an additional cohort of patients with IPF. Lrp5 null mice were protected against bleomycin-induced pulmonary fibrosis, an effect that was phenocopied by direct inhibition of beta-catenin signaling by the small molecular inhibitor of beta-catenin responsive transcription. Transplantation of Lrp5 null bone marrow cells into wild-type mice did not limit fibrosis. Instead, Lrp5 loss was associated with reduced TGF-beta production by alveolar type 2 cells and leukocytes. Consistent with a role of Lrp5 in the activation of TGF-beta, Lrp5 null mice were not protected against lung fibrosis induced by TGF-beta.Conclusions: We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-beta signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.