Brain Advance Access originally published online on August 5, 2006
Brain 2006 129(9):2404-2415; doi:10.1093/brain/awl192
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TGFß receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis
1 Clinical Immunology, University Hospital Zurich Zurich, Switzerland 2 Institute of Laboratory Animal Science, University of Zurich Zurich, Switzerland 3 Department of Pathology and Immunology, Centre Médicale Universitaire (CMU) Geneva, Switzerland 4 Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University Munich, Germany 5 Department of Molecular Medicine and Gene Therapy, Lund University Lund, Sweden
Correspondence to: Adriano Fontana, Clinical Immunology, University Hospital Zurich, Häldeliweg 4, CH-8044 Zurich, Switzerland E-mail: adriano.fontana{at}usz.ch
In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1ß (IL-1ß). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFß) is a potent deactivator of PMN and macrophages since TGFß suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFß receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFß receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFß was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFß receptor II. L-Selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFß signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.
Key Words: innate immunity; stroke; neuronal injury; blood brain barrier; chemokines
Abbreviations: BBB, blood–brain barrier; BSA, bovine serum albumin; cfu, colony-forming units; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorter; FITC, fluoroisothiocyanate; ICP, intracranial pressure; LPS, lipopolysaccharide; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PEC, peritoneal exudate cells; PMN, polymorphonuclear leucocytes; RT–PCR, reverse transcription–polymerase chain reaction; TGFß, transforming growth factor beta; TLRs, Toll-like receptors
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Received January 24, 2006. Revised June 1, 2006. Accepted June 1, 2006.
*These two authors have contributed equally to this work.
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