Christina Wache1, Matthias Klein1, Christian Ostergaard2, Barbara Angele1, Hans Häcker3, Hans-Walter Pfister1, Monika Pruenster4, Markus Sperandio4, Tomas Leanderson5, Johannes Roth6, Thomas Vogl6, Uwe Koedel1. 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.
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 mousemeningitis model, using MRP14-deficientmice. 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-deficientmice 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-deficientmice 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.
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