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Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis.

Geldhoff M, Mook-Kanamori BB, Brouwer MC, Troost D, Leemans JC, Flavell RA, Van der Ende A, Van der Poll T, Van de Beek D - BMC Infect. Dis. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.

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Cytokine levels in blood and brain homogenate. Cytokines were measured in WT (n = 11), Nlrp3−/− (n = 12) and Asc−/− (n = 12) mice in blood (A, C) and brain homogenate (WT; n = 7, Nlrp3−/−; n = 8, Asc−/−; n = 8) (B, D) at 30 hours after induction of pneumococcal meningitis. Undisplayed cytokines measurement did not differ significantly between Nlrp3−/− or Asc−/− and WT mice. Data are given as medians and 75th quartile. * P < 0.05.
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Figure 4: Cytokine levels in blood and brain homogenate. Cytokines were measured in WT (n = 11), Nlrp3−/− (n = 12) and Asc−/− (n = 12) mice in blood (A, C) and brain homogenate (WT; n = 7, Nlrp3−/−; n = 8, Asc−/−; n = 8) (B, D) at 30 hours after induction of pneumococcal meningitis. Undisplayed cytokines measurement did not differ significantly between Nlrp3−/− or Asc−/− and WT mice. Data are given as medians and 75th quartile. * P < 0.05.

Mentions: Nlrp3−/− mice showed decreased plasma levels of MIP-2 (median 12 pg/ml [IQR 5–20] versus 55 pg/ml [IQR 5–77], p=0.037) and IL-6 (52 pg/ml [IQR 24–90] versus 191 pg/ml [70–306], p=0.019) at 30 h as compared to WT mice (Figure 4A). No significant cytokine differences were found at 6 hours. Asc−/− mice showed decreased plasma levels of MIP-2 (12 pg/ml [IQR 5–27] versus 55 pg/ml [IQR 35–80] pg/ml, p=0.01), IL-6 (37 pg/ml [IQR 24–108] versus 202 pg/ml [IQR 46–448], p=0.034) and IFN- γ (3 pg/ml [3] versus 16 pg/ml [3-24], p=0.005) at 30 h, as compared to WT mice. At 6 h only KC levels were lower (105 pg/ml [78–202] versus 186 pg/ml [151–388], p=0.005). Notably, plasma levels of IL-1β and IL-18 were similar in Nlrp3−/−, Asc−/− and WT mice (Figure 4C). For the other measured cytokines no significant difference was found at 6 or 30 hours.


Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis.

Geldhoff M, Mook-Kanamori BB, Brouwer MC, Troost D, Leemans JC, Flavell RA, Van der Ende A, Van der Poll T, Van de Beek D - BMC Infect. Dis. (2013)

Cytokine levels in blood and brain homogenate. Cytokines were measured in WT (n = 11), Nlrp3−/− (n = 12) and Asc−/− (n = 12) mice in blood (A, C) and brain homogenate (WT; n = 7, Nlrp3−/−; n = 8, Asc−/−; n = 8) (B, D) at 30 hours after induction of pneumococcal meningitis. Undisplayed cytokines measurement did not differ significantly between Nlrp3−/− or Asc−/− and WT mice. Data are given as medians and 75th quartile. * P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750264&req=5

Figure 4: Cytokine levels in blood and brain homogenate. Cytokines were measured in WT (n = 11), Nlrp3−/− (n = 12) and Asc−/− (n = 12) mice in blood (A, C) and brain homogenate (WT; n = 7, Nlrp3−/−; n = 8, Asc−/−; n = 8) (B, D) at 30 hours after induction of pneumococcal meningitis. Undisplayed cytokines measurement did not differ significantly between Nlrp3−/− or Asc−/− and WT mice. Data are given as medians and 75th quartile. * P < 0.05.
Mentions: Nlrp3−/− mice showed decreased plasma levels of MIP-2 (median 12 pg/ml [IQR 5–20] versus 55 pg/ml [IQR 5–77], p=0.037) and IL-6 (52 pg/ml [IQR 24–90] versus 191 pg/ml [70–306], p=0.019) at 30 h as compared to WT mice (Figure 4A). No significant cytokine differences were found at 6 hours. Asc−/− mice showed decreased plasma levels of MIP-2 (12 pg/ml [IQR 5–27] versus 55 pg/ml [IQR 35–80] pg/ml, p=0.01), IL-6 (37 pg/ml [IQR 24–108] versus 202 pg/ml [IQR 46–448], p=0.034) and IFN- γ (3 pg/ml [3] versus 16 pg/ml [3-24], p=0.005) at 30 h, as compared to WT mice. At 6 h only KC levels were lower (105 pg/ml [78–202] versus 186 pg/ml [151–388], p=0.005). Notably, plasma levels of IL-1β and IL-18 were similar in Nlrp3−/−, Asc−/− and WT mice (Figure 4C). For the other measured cytokines no significant difference was found at 6 or 30 hours.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus