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TRAIL limits excessive host immune responses in bacterial meningitis
Olaf Hoffmann, … , Frauke Zipp, Joerg R. Weber
Olaf Hoffmann, … , Frauke Zipp, Joerg R. Weber
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):2004-2013. https://doi.org/10.1172/JCI30356.
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Research Article Infectious disease Article has an altmetric score of 3

TRAIL limits excessive host immune responses in bacterial meningitis

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Abstract

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.

Authors

Olaf Hoffmann, Josef Priller, Timour Prozorovski, Ulf Schulze-Topphoff, Nevena Baeva, Jan D. Lunemann, Orhan Aktas, Cordula Mahrhofer, Sarah Stricker, Frauke Zipp, Joerg R. Weber

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Figure 5

Myeloid cells are the source of TRAIL in experimental meningitis.

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Myeloid cells are the source of TRAIL in experimental meningitis.
(A) In...
(A) In BM chimeric mice, the degree of chimerism was assessed by FACS analysis of peripheral blood leukocytes. Histogram plot demonstrates strong enhanced GFP expression in leukocyte populations from a chimera compared with that in leukocytes from a nontransplanted mouse. (B) The degree of CSF inflammation at 24 hours after meningitis induction in BM chimeric mice is determined by the genotype of the BM donor. Note that the levels of chimerism were comparable among all 4 groups of chimeras. CSF pleocytosis correlated negatively with TRAIL deficiency in hematopoietic cells. (C) Real-time PCR revealed presence of TRAIL mRNA in wild-type and TRAIL–/– mice transplanted with wild-type BM (C57/C57 and TRAIL–/–/C57, respectively) but absence of TRAIL mRNA expression in TRAIL–/– mice transplanted with TRAIL–/– BM (TRAIL–/–/TRAIL–/–). bps, base pairs.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 19 patents
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