Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment
Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment
复制标题
颗粒体蛋白前体通过促进巨噬细胞募集在脓毒症期间的宿主防御中发挥核心作用。
DOI：
10.1164/rccm.201601-0056oc
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发表时间：
2016-11-15
影响因子：
24.7
通讯作者：
Cao, Ju
中科院分区：
文献类型：
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作者：
Song, Zhixin;Zhang, Xuemei;Cao, Ju
原理：颗粒蛋白原是一种广泛表达的蛋白质，具有多种生理功能。颗粒蛋白前体在宿主对脓毒症反应中的功能作用仍不清楚。目的：评估颗粒蛋白前体在宿主对脓毒症反应中的作用。方法：测定颗粒蛋白前体对宿主对脓毒症反应的影响。测量和主要结果：相对于相应的健康成人（n = 26），成人（n = 74）和儿童（n = 26）脓毒症患者的颗粒蛋白前体浓度显著升高。36）和儿科（n = 17）对照受试者。通过使用非严重脓毒症的低致死率模型，我们观察到颗粒蛋白前体缺乏不仅增加死亡率，而且减少脓毒症期间的细菌清除。在前颗粒蛋白缺陷小鼠中，宿主对脓毒症的防御能力降低与巨噬细胞募集减少有关，在脓毒症早期，腹腔灌洗液中的趋化因子CC受体配体2（CCL2）产生相应受损。来源于造血细胞的颗粒蛋白前体有助于脓毒症中的宿主防御。重组前颗粒蛋白的治疗性给药不仅挽救了非严重脓毒症后前颗粒蛋白缺陷小鼠受损的宿主防御，而且还保护了野生型小鼠免受严重脓毒症的高致死率模型的伤害。前粒蛋白介导的对脓毒症的保护与改善腹腔巨噬细胞募集密切相关。此外，CCL2治疗progranulin缺陷小鼠提高生存率和减少腹腔细菌负荷脓毒症，至少部分通过促进腹腔巨噬细胞recruitment.Conclusions：这个概念验证研究支持的核心作用progranulin依赖的巨噬细胞招聘在主机防御脓毒症，开辟新的机会，以主机为导向的治疗策略，操纵主机的免疫反应在脓毒症的治疗。
Rationale: Progranulin, a widely expressed protein, has multiple physiological functions. The functional role of progranulin in the host response to sepsis remains unknown.Objectives: To assess the role of progranulin in the host response to sepsis.Methods: Effects of progranulin on host response to sepsis were determined.Measurements and Main Results: Progranulin concentrations were significantly elevated in adult (n = 74) and pediatric (n = 26) patients with sepsis relative to corresponding healthy adult (n = 36) and pediatric (n = 17) control subjects, respectively. By using a low lethality model of nonsevere sepsis, we observed that progranulin deficiency not only increased mortality but also decreased bacterial clearance during sepsis. The decreased host defense to sepsis in progranulin-deficient mice was associated with reduced macrophage recruitment, with correspondingly impaired chemokine CC receptor ligand 2 (CCL2) production in peritoneal lavages during the early phase of sepsis. Progranulin derived from hematopoietic cells contributed to host defense in sepsis. Therapeutic administration of recombinant progranulin not only rescued impaired host defense in progranulin-deficient mice after nonsevere sepsis but also protected wild-type mice against a high-lethality model of severe sepsis. Progranulin-mediated protection against sepsis was closely linked to improved peritoneal macrophage recruitment. In addition, CCL2 treatment of progranulin-deficient mice improved survival and decreased peritoneal bacterial loads during sepsis, at least in part through promotion of peritoneal macrophage recruitment.Conclusions: This proof-of-concept study supports a central role of progranulin-dependent macrophage recruitment in host defense to sepsis, opening new opportunities to host-directed therapeutic strategy that manipulate host immune response in the treatment of sepsis.