title: Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment.
abstract: 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.
authors.affiliation: 1 Department of Laboratory Medicine.|2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Song
authors.affiliation: 2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 1 Department of Laboratory Medicine.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 3 Department of Emergency and Intensive Care Unit.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: 2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
authors.forename: Xintong
authors.initials: X
authors.lastname: Tao
authors.affiliation: 4 Department of Obstetrics and Gynecology, and.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1 Department of Laboratory Medicine.
authors.forename: Xue
authors.initials: X
authors.lastname: Lin
authors.affiliation: 2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
authors.forename: Lihua
authors.initials: L
authors.lastname: Kang
authors.affiliation: 1 Department of Laboratory Medicine.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: 1 Department of Laboratory Medicine.
authors.forename: Xaiofei
authors.initials: X
authors.lastname: Lai
authors.affiliation: 5 Clinical Laboratories Center, Affiliated Children's Hospital of Chongqing Medical University, Chongqing, China; and.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 6 Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: 7 Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Dai
authors.affiliation: 2 Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, and.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yin
authors.affiliation: 1 Department of Laboratory Medicine.
authors.forename: Ju
authors.initials: J
authors.lastname: Cao
mesh_terms: D000328:Adult; D000818:Animals; D002648:Child; D005260:Female; D000077155:Granulins; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077153:Progranulins; D018805:Sepsis / Q000097:blood* / Q000276:immunology*
chemical_list: C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: host response; macrophages; progranulin; protection; sepsis