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: Christina Wache, Matthias Klein, Christian Ostergaard, Barbara Angele, Hans Häcker, Hans-Walter Pfister, Monika Pruenster, Markus Sperandio, Tomas Leanderson, Johannes Roth, Thomas Vogl, Uwe Koedel
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 212 Issue 2 Pg. 247-57 (Jul 15 2015) ISSN: 1537-6613 [Electronic] United States
• PMID: 25605866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• ABCC11 protein, human
• ATP-Binding Cassette Transporters
• Anti-Bacterial Agents
• Calgranulin B
• Chemokine CXCL2
• Ceftriaxone

Topics

• ATP-Binding Cassette Transporters (cerebrospinal fluid)
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Calgranulin B (cerebrospinal fluid)
• Case-Control Studies
• Ceftriaxone (pharmacology, therapeutic use)
• Chemokine CXCL2 (biosynthesis)
• Humans
• Male
• Meningitis, Pneumococcal (cerebrospinal fluid, drug therapy, immunology)
• Mice, Inbred C57BL
• Mice, Knockout