Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice
Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice
复制标题
DOI：
10.1371/journal.ppat.1008823
复制
发表时间：
2020-08-01
期刊：
影响因子：
6.7
通讯作者：
Sakaguchi, Suehiro
中科院分区：
文献类型：
--
作者：
Chida, Junji;Hara, Hideyuki;Sakaguchi, Suehiro
细胞朊病毒蛋白PrP（c）是一种糖基磷脂酰肌醇透膜糖蛋白，在神经元细胞中表达最丰富，在非神经元细胞中表达较少。它在神经元中构象转化为淀粉样蛋白异构体是朊病毒疾病的关键致病事件，包括人类的克雅氏病和动物的羊瘙痒病和牛海绵状脑病。然而，PrP（c）的正常功能在很大程度上仍然未知，特别是在非神经元细胞中。在这里，我们表明，用抗PrP单克隆抗体（mAb）刺激PrP（c）可保护小鼠免受甲型流感病毒（IAV）的致死性感染，在感染的肺中具有激活的Src家族激酶（SFKs）的抗炎M2巨噬细胞的大量积累。SFK抑制剂达沙替尼在用抗PrP mAb治疗后抑制IAV感染的肺中的M2巨噬细胞积聚，并消除抗PrP mAb诱导的对小鼠致死性流感感染的保护活性。我们还发现在体外和体内用抗PrP单克隆抗体刺激PrP（c）可通过激活SFK诱导腹腔巨噬细胞M2极化。这些结果表明，PrP（c）可以激活SFK在巨噬细胞和诱导巨噬细胞极化的抗炎M2表型后，刺激与抗PrP单克隆抗体，从而引发保护活性，对致死性感染的IAV小鼠后，与抗PrP单克隆抗体治疗。这些结果也突出了PrP（c）作为IAV infection.Author总结的一个新的治疗靶点。我们在这里表明，用抗PrP单克隆抗体刺激PrP（c），通过激活感染肺中的SFKs，刺激巨噬细胞极化为抗炎M2表型，从而保护小鼠免受IAV的致死性感染。IAV是流感季节性流行爆发的病原体，并且通常在感染者中引起高发病率和死亡率，特别是在年轻人和老年人以及患有基础慢性疾病的人中。还据报道，高致病性禽IAV有可能感染人类并在感染个体中引起高发病率和死亡率。IAV感染的另一个问题是，新的IAV毒株已在人群中出现，这些毒株对目前可用的抗流感药物（例如神经氨酸酶抑制剂）具有耐药性。我们目前的研究结果表明，用抗PrP mAb靶向PrP（c）可保护小鼠免受IAV的致死性感染，这可能导致PrP（c）靶向治疗可能对流感感染有益。此外，由于PrP（c）是宿主分子，因此PrP（c）靶向药物可能不会诱导耐药IAV。因此，PrP（c）可能是一种新的靶分子，用于治疗IAV感染，但需要进一步的研究。
The cellular prion protein, PrP (c), is a glycosylphosphatidylinositol anchored-membrane glycoprotein expressed most abundantly in neuronal and to a lesser extent in non-neuronal cells. Its conformational conversion into the amyloidogenic isoform in neurons is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. However, the normal functions of PrP (c) remain largely unknown, particularly in non-neuronal cells. Here we show that stimulation of PrP (c) with anti-PrP monoclonal antibodies (mAbs) protected mice from lethal infection with influenza A viruses (IAVs), with abundant accumulation of anti-inflammatory M2 macrophages with activated Src family kinases (SFKs) in infected lungs. A SFK inhibitor dasatinib inhibited M2 macrophage accumulation in IAV-infected lungs after treatment with anti-PrP mAbs and abolished the anti-PrP mAb-induced protective activity against lethal influenza infection in mice. We also show that stimulation of PrP (c) with anti-PrP mAbs induced M2 polarization in peritoneal macrophages through SFK activationin vitroandin vivo. These results indicate that PrP (c) could activate SFK in macrophages and induce macrophage polarization to an anti-inflammatory M2 phenotype after stimulation with anti-PrP mAbs, thereby eliciting protective activity against lethal infection with IAVs in mice after treatment with anti-PrP mAbs. These results also highlight PrP (c) as a novel therapeutic target for IAV infection.Author summary We show here that stimulation of PrP (c) with anti-PrP mAbs protected mice from lethal infection with IAVs by stimulating macrophage polarization to an anti-inflammatory M2 phenotype through activation of SFKs in infected lungs. IAVs are causative agents for seasonal epidemic outbreaks of influenza, and often cause high morbidity and mortality in infected people, particularly in the young and elderly and those with underlying chronic diseases. It has also been reported that highly pathogenic avian IAVs have the potential to infect humans and cause high morbidity and mortality in infected individuals. The other problem with IAV infections is that new IAV strains, which are resistant to currently available anti-influenza agents such as neuraminidase inhibitors, have been emerging in human populations. Our current results showing that targeting PrP (c) with anti-PrP mAbs protected against lethal infection with IAVs in mice gives rise to the possibility that PrP (c)-targeting therapeutics might be beneficial in influenza infection. Moreover, since PrP (c) is a host molecule, PrP (c)-targeting drugs might not induce drug-resistant IAVs. Thus, PrP (c) might be a novel target molecule for therapeutic development for IAV infection, although further studies are needed.