title: Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis.
abstract: BACKGROUND
  Inflammasomes are multi-protein intracellular signaling complexes that have recently been hypothesized to play a role in the regulation of the inflammation response. We studied associations between inflammasome-associated cytokines IL-1β and IL-18 in cerebrospinal fluid (CSF) of patients with bacterial meningitis and clinical outcome, and pneumococcal serotype. In a murine model of pneumococcal meningitis we examined the pathophysiological roles of two inflammasome proteins, NLRP3 (Nod-like receptor protein-3) and adaptor protein ASC (apoptosis-associated speck-like protein).
  
  
  METHODS
  In a nationwide prospective cohort study, CSF cytokine levels were measured and related to clinical outcome and pneumococcal serotype. In a murine model of pneumococcal meningitis using Streptococcus pneumoniae serotype 3, we examined bacterial titers, cytokine profiles and brain histology at 6 and 30 hours after inoculation in wild-type (WT), Asc and Nlrp3 deficient mice.
  
  
  RESULTS
  In patients with bacterial meningitis, CSF levels of inflammasome associated cytokines IL-1β and IL-18 were related to complications, and unfavorable disease outcome. CSF levels of IL-1β were associated with pneumococcal serotype (p<0.001). In our animal model, Asc and Nlrp3 deficient mice had decreased systemic inflammatory responses and bacterial outgrowth as compared to WT mice. Differences between Asc⁻/⁻ and WT mice appeared sooner after bacterial inoculation and were more widespread (lower pro-inflammatory cytokine levels in both blood and brain homogenate) than in Nlrp3⁻/⁻ mice. Nlrp3 deficiency was associated with an increase of cerebral neutrophil infiltration and cerebral hemorrhages when compared to WT controls.
  
  
  CONCLUSIONS
  Our results implicate an important role for inflammasome proteins NLRP3 and ASC in the regulation of the systemic inflammatory response and the development of cerebral damage during pneumococcal meningitis, which may dependent on the pneumococcal serotype.
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Madelijn
authors.initials: M
authors.lastname: Geldhoff
authors.forename: Barry B
authors.initials: BB
authors.lastname: Mook-Kanamori
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Jaklien C
authors.initials: JC
authors.lastname: Leemans
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Arie
authors.initials: A
authors.lastname: Van der Ende
authors.forename: Tom
authors.initials: T
authors.lastname: Van der Poll
authors.forename: Diederik
authors.initials: D
authors.lastname: Van de Beek
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001923:Brain Chemistry; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D013296:Streptococcus pneumoniae / Q000302:isolation & purification; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse
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