1 Department of Laboratory Medicine.
2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
Am J Respir Crit Care Med. 2016 Nov 15;194(10):1219-1232. doi: 10.1164/rccm.201601-0056OC.
Progranulin, a widely expressed protein, has multiple physiological functions. The functional role of progranulin in the host response to sepsis remains unknown.
To assess the role of progranulin in the host response to sepsis.
Effects of progranulin on host response to sepsis were determined.
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.
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.
颗粒蛋白前体（一种广泛表达的蛋白）具有多种生理功能。但其在宿主对脓毒症反应中的功能作用尚不清楚。
评估颗粒蛋白前体在宿主对脓毒症反应中的作用。
检测颗粒蛋白前体对宿主对脓毒症反应的影响。
与相应的健康成人（n=36）和儿科（n=17）对照组相比，成人（n=74）和儿科（n=26）脓毒症患者的颗粒蛋白前体浓度显著升高。在非严重脓毒症的低致死性模型中，我们发现颗粒蛋白前体缺乏不仅增加了死亡率，而且还降低了脓毒症期间的细菌清除率。颗粒蛋白前体缺陷小鼠对脓毒症的宿主防御能力降低与巨噬细胞募集减少有关，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。来自造血细胞的颗粒蛋白前体有助于脓毒症中的宿主防御。重组颗粒蛋白前体的治疗性给药不仅挽救了非严重脓毒症后颗粒蛋白前体缺陷小鼠受损的宿主防御，而且还保护野生型小鼠免受严重脓毒症的高致死性模型的影响。颗粒蛋白前体介导的脓毒症保护作用与改善腹膜巨噬细胞募集密切相关。此外，CCL2 治疗颗粒蛋白前体缺陷小鼠可改善脓毒症期间的存活率并减少腹腔细菌负荷，至少部分是通过促进腹膜巨噬细胞募集来实现的。
本概念验证研究支持颗粒蛋白前体依赖性巨噬细胞募集在宿主对脓毒症的防御中的核心作用，为操纵宿主免疫反应的宿主定向治疗策略提供了新的机会，从而为脓毒症的治疗提供了新的机会。
