Journal
ANNALS OF NEUROLOGY
Volume 51, Issue 3, Pages 319-329Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.10103
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Caspase 1 plays a pivotal role in generating mature cytokine interieukin-1beta. Interleukin-1beta 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 interieukin-1beta. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis-induced increase in interleukin-lbeta. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiflammatory 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.
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