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J Infect Dis. 2015 Jul 15;212(2):247-57. doi: 10.1093/infdis/jiv028. Epub 2015 Jan 20.

Myeloid-related protein 14 promotes inflammation and injury in meningitis.

Author information

1
Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University.
2
Department of Clinical Microbiology, Copenhagen University Hospital Hvidovre, Denmark.
3
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.
4
Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University, München.
5
Immunology Group, University of Lund, Sweden.
6
Institute of Immunology, Westfälische Wilhelms-Universität Münster, Germany.

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.

KEYWORDS:

S100A8/S100A9; calprotectin; central nervous system infection; danger-associated molecular pattern; innate immune response; resolution of inflammation

PMID:
25605866
DOI:
10.1093/infdis/jiv028
[Indexed for MEDLINE]

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