title: Progranulin is a chemoattractant for microglia and stimulates their endocytic activity.
abstract: Mutations resulting in progranulin haploinsufficiency cause disease in patients with a subset of frontotemporal lobar degeneration; however, the biological functions of progranulin in the brain remain unknown. To address this subject, the present study initially assessed changes in gene expression and cytokine secretion in rat primary cortical neurons treated with progranulin. Molecular pathways enriched in the progranulin gene set included cell adhesion and cell motility pathways and pathways involved in growth and development. Secretion of cytokines and several chemokines linked to chemoattraction but not inflammation were also increased from progranulin-treated primary neurons. Therefore, whether progranulin is involved in recruitment of immune cells in the brain was investigated. Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of Iba1-positive microglia around the injection site. Moreover, progranulin alone was sufficient to promote migration of primary mouse microglia in vitro. Primary microglia and C4B8 cells demonstrated more endocytosis of amyloid β1-42 when treated with progranulin. These data demonstrate that progranulin acts as a chemoattractant in the brain to recruit or activate microglia and can increase endocytosis of extracellular peptides such as amyloid β.
authors.affiliation: Department of Neuroscience Drug Discovery, Merck Research Laboratories, Boston, Massachusetts 02115, USA. fiona_pickford@merck.com
authors.forename: Fiona
authors.initials: F
authors.lastname: Pickford
authors.forename: Jacob
authors.initials: J
authors.lastname: Marcus
authors.forename: Luiz Miguel
authors.initials: LM
authors.lastname: Camargo
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Xiao
authors.forename: Danielle
authors.initials: D
authors.lastname: Graham
authors.forename: Jan-Rung
authors.initials: JR
authors.lastname: Mo
authors.forename: Matthew
authors.initials: M
authors.lastname: Burkhardt
authors.forename: Vinayak
authors.initials: V
authors.lastname: Kulkarni
authors.forename: Jamie
authors.initials: J
authors.lastname: Crispino
authors.forename: Heike
authors.initials: H
authors.lastname: Hering
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002630:Chemotactic Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D000077153:Progranulins; D051381:Rats
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D002630:Chemotactic Factors; D016207:Cytokines; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D000077153:Progranulins