title: Myeloid-related protein 14 promotes inflammation and injury in meningitis.
abstract: BACKGROUND
  Neutrophilic inflammation often persists for days despite effective antibiotic treatment and contributes to brain damage in bacterial meningitis. We propose here that myeloid-related protein 14 (MRP14), an abundant cytosolic protein in myeloid cells, acts as an endogenous danger signal, driving inflammation and aggravating tissue injury.
  
  
  METHODS
  The release pattern of MRP14 was analyzed in human and murine cerebrospinal fluid (CSF), as well as in isolated neutrophils. Its functional role was assessed in a mouse meningitis model, using MRP14-deficient mice.
  
  
  RESULTS
  We detected large quantities of MRP14 in CSF specimens from patients and mice with pneumococcal meningitis. Immunohistochemical analyses and a cell-depletion approach indicated neutrophils as the major source of MRP14. In a meningitis model, MRP14-deficient mice showed a better resolution of inflammation during antibiotic therapy, which was accompanied by reduced disease severity. Intrathecal administration of MRP14 before infection reverted the phenotype of MRP14-deficient mice back to wild type. Moreover, intrathecal injection of MRP14 alone was sufficient to induce meningitis in a Toll-like receptor 4 (TLR4)-CXCL2-dependent manner. Finally, treatment with the MRP14 antagonist paquinimod reduced inflammation and disease severity significantly, reaching levels comparable to those achieved after genetic depletion of MRP14.
  
  
  CONCLUSIONS
  The present study implicates MRP14 as an essential propagator of inflammation and potential therapeutic target in pneumococcal meningitis.
authors.affiliation: Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
authors.forename: Christina
authors.initials: C
authors.lastname: Wache
authors.affiliation: Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Ostergaard
authors.affiliation: Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
authors.forename: Barbara
authors.initials: B
authors.lastname: Angele
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Hans
authors.initials: H
authors.lastname: Häcker
authors.affiliation: Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.affiliation: Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University, München.
authors.forename: Monika
authors.initials: M
authors.lastname: Pruenster
authors.affiliation: Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University, München.
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.affiliation: Immunology Group, University of Lund, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.affiliation: Institute of Immunology, Westfälische Wilhelms-Universität Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Immunology, Westfälische Wilhelms-Universität Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000134:cerebrospinal fluid; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D040502:Calgranulin B / Q000134:cerebrospinal fluid*; D016022:Case-Control Studies; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D040502:Calgranulin B; D054426:Chemokine CXCL2; D002443:Ceftriaxone
keywords: S100A8/S100A9; calprotectin; central nervous system infection; danger-associated molecular pattern; innate immune response; resolution of inflammation