title: Lymphocytes modulate innate immune responses and neuronal damage in experimental meningitis.
abstract: In bacterial meningitis, excessive immune responses carry significant potential for damage to brain tissue even after successful antibiotic therapy. Bacterial meningitis is regarded primarily as the domain of innate immunity, and the role of lymphocytes remains unclear. We studied the contribution of lymphocytes to acute inflammation and neurodegeneration in experimental Toll-like receptor 2-driven meningitis, comparing wild-type mice with RAG-1-deficient mice that have no mature T and B lymphocytes. At 24 h after intrathecal challenge with the synthetic bacterial lipopeptide Pam(3)CysSK(4), RAG-1-deficient mice displayed more pronounced clinical impairment and an increased concentration of neutrophils, reduced expression of interleukin-10 (IL-10) mRNA, and increased expression of CXCL1 mRNA in the cerebrospinal fluid. Conversely, neuronal loss in the dentate gyrus was reduced in RAG-1-deficient mice, and expression of IL-10, transforming growth factor β and CCL2 mRNA by microglia was increased compared to wild-type mice. Adoptive transfer of wild-type lymphocytes reversed the enhanced meningeal inflammation and functional impairment observed in RAG-1-deficient mice. Our findings suggest compartment-specific effects of lymphocytes during acute bacterial meningitis, including attenuation of meningeal inflammation and shifting of microglial activation toward a more neurotoxic phenotype.
authors.affiliation: Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany Department of Neurology, St. Josefs-Krankenhaus, Potsdam, Germany o.hoffmann@alexius.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Hoffmann
authors.affiliation: Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Rung
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Josephin
authors.initials: J
authors.lastname: Held
authors.affiliation: Laboratory of Molecular Psychiatry and Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Chotima
authors.initials: C
authors.lastname: Boettcher
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prokop
authors.affiliation: Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Laboratory of Molecular Psychiatry and Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate; D008214:Lymphocytes / Q000276:immunology*; D016920:Meningitis, Bacterial / Q000276:immunology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein