title: Pleiotrophin regulates microglia-mediated neuroinflammation.
abstract: Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved.
  
  
  
  In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO).
  
  
  
  We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS.
  
  
  
  Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Fernández-Calle
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicente-Rodríguez
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gramage
authors.affiliation: Biochemistry and Molecular Biology lab, Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Jimena
authors.initials: J
authors.lastname: Pita
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-García
authors.affiliation: BRAINco Biopharma, S.L., Bizkaia Technology Park, Vizcaya, Spain.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ferrer-Alcón
authors.affiliation: BRAINco Biopharma, S.L., Bizkaia Technology Park, Vizcaya, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Uribarri
authors.affiliation: Biochemistry and Molecular Biology lab, Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Ramos
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain. herradon@ceu.es.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Herradón
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D017397:Prefrontal Cortex / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; C066845:pleiotrophin; D009569:Nitric Oxide
keywords: Microglia activation; Microgliosis; Midkine; Neuroimmune response; Neuroinflammation; Pleiotrophin; TLR4