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Role of Caspase‐1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase‐1‐deficient mice
Author(s) -
Koedel Uwe,
Winkler Frank,
Angele Barbara,
Fontana Adriano,
Flavell Richard A.,
Pfister HansWalter
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10103
Subject(s) - caspase 1 , meningitis , cerebrospinal fluid , downregulation and upregulation , blockade , immunology , medicine , caspase 3 , caspase , interleukin , cytokine , inflammation , apoptosis , biology , inflammasome , gene , programmed cell death , receptor , surgery , biochemistry
Caspase 1 plays a pivotal role in generating mature cytokine interleukin‐1β. Interleukin‐1β is implicated as a mediator of pneumococcal meningitis, both in experimental models and in humans. We demonstrated here that (1) Caspase 1 mRNA and protein expression is upregulated in the brain during experimental pneumococcal meningitis, and (2) Caspase 1 levels are elevated in the cerebrospinal fluid of patients with acute bacterial meningitis. The upregulation/activation of Caspase 1 was associated with increased levels of interleukin‐1β. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis‐induced increase in interleukin‐1β. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiinflammatory effect of Caspase 1 depletion or blockade was associated with a marked reduction of meningitis‐induced intracranial complications, thus leading to an improved clinical status. In humans, cerebrospinal fluid Caspase 1 levels correlated with the clinical outcome. Thus, pharmacologic inhibition may provide an efficient adjuvant therapeutic strategy in this disease.