TRAIL limits excessive host immune responses in bacterial meningitis.
Apart from potential roles in anti-tumor surveillance, the TNF-related apoptosis-inducing ligand (TRAIL) has important regulatory functions in the host immune response. We studied antiinflammatory effects of endogenous and recombinant TRAIL (rTRAIL) in experimental meningitis. Following intrathecal application of pneumococcal cell wall, a TLR2 ligand, we found prolonged inflammation, augmented clinical impairment, and increased apoptosis in the hippocampus of TRAIL(-/-) mice. Administration of rTRAIL into the subarachnoid space of TRAIL(-/-) mice or reconstitution of hematopoiesis with wild-type bone marrow cells reversed these effects, suggesting an autoregulatory role of TRAIL within the infiltrating leukocyte population. Importantly, intrathecal application of rTRAIL in wild-type mice with meningitis also decreased inflammation and apoptosis. Moreover, patients suffering from bacterial meningitis showed increased intrathecal synthesis of TRAIL. Our findings provide what we believe is the first evidence that TRAIL may act as a negative regulator of acute CNS inflammation. The ability of TRAIL to modify inflammatory responses and to reduce neuronal cell death in meningitis suggests that it may be used as a novel antiinflammatory agent in invasive infections.
Hoffmann
Olaf
O
Department of Neurology, Laboratory of Molecular Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany.
Priller
Josef
J
Prozorovski
Timour
T
Schulze-Topphoff
Ulf
U
Baeva
Nevena
N
Lunemann
Jan D
JD
Aktas
Orhan
O
Mahrhofer
Cordula
C
Stricker
Sarah
S
Zipp
Frauke
F
Weber
Joerg R
JR
D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D002470:Cell Survival; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D006095:Gram-Positive Cocci / Q000502:physiology; D006098:Granulocytes / Q000378:metabolism; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007962:Leukocytes / Q000166:cytology; D008297:Male; D016920:Meningitis, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009343:Neisseria / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology
D018821:CD18 Antigens; D016207:Cytokines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand