Limits...
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.

Show MeSH

Related in: MedlinePlus

Histopathology in Asc−/−, Nlrp3−/−, and WT mice with pneumococcal meningitis. Representative brain slides showing neutrophil infiltration in the meninges 30 hours after induction of pneumococcal meningitis in a WT mouse (A), Asc−/− mouse (B) and Nlrp3−/− mouse (C). Perivascular cuffing 30 hours after induction of pneumococcal meningitis in a WT mouse (D), Asc−/− mouse (E) and Nlrp3−/− mouse (F), showing frequent intracerebral and subpial hemorrhages associated with neutrophil infiltration; meningeal, perivascular and intracerebral neutrophil influx was scored on a scale 0–4, means of 16 brain slides per mouse in the coronal plane are displayed (WT, n = 11; Asc−/−, n = 8; Nlrp3−/−, n = 9; G). Sum of intracerebral hemorrhages and subpial hemorrhages per mouse (WT, n = 11; Asc−/−; n = 8; Nlrp3−/−; n = 9; H).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750264&req=5

Figure 5: Histopathology in Asc−/−, Nlrp3−/−, and WT mice with pneumococcal meningitis. Representative brain slides showing neutrophil infiltration in the meninges 30 hours after induction of pneumococcal meningitis in a WT mouse (A), Asc−/− mouse (B) and Nlrp3−/− mouse (C). Perivascular cuffing 30 hours after induction of pneumococcal meningitis in a WT mouse (D), Asc−/− mouse (E) and Nlrp3−/− mouse (F), showing frequent intracerebral and subpial hemorrhages associated with neutrophil infiltration; meningeal, perivascular and intracerebral neutrophil influx was scored on a scale 0–4, means of 16 brain slides per mouse in the coronal plane are displayed (WT, n = 11; Asc−/−, n = 8; Nlrp3−/−, n = 9; G). Sum of intracerebral hemorrhages and subpial hemorrhages per mouse (WT, n = 11; Asc−/−; n = 8; Nlrp3−/−; n = 9; H).

Mentions: Neutrophil infiltrate in the brain was more pronounced in Nlrp3−/− mice at 30 h after inoculation as compared to WT mice (median score 1.5 versus 2.4, p=0.018; Figure 5G). Nlrp3−/− mice also showed an elevated number of intracerebral and subpial hemorrhages and as compared to WT mice (median 12.5 versus 1.0 per slide, p=0.02; Figure 5H). Asc−/− mice showed no difference in neutrophil influx score and intracerebral hemorrhages compared to WT mice. Brain MPO levels were similar in both knockouts and wild-type mice (data not shown).


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)

Histopathology in Asc−/−, Nlrp3−/−, and WT mice with pneumococcal meningitis. Representative brain slides showing neutrophil infiltration in the meninges 30 hours after induction of pneumococcal meningitis in a WT mouse (A), Asc−/− mouse (B) and Nlrp3−/− mouse (C). Perivascular cuffing 30 hours after induction of pneumococcal meningitis in a WT mouse (D), Asc−/− mouse (E) and Nlrp3−/− mouse (F), showing frequent intracerebral and subpial hemorrhages associated with neutrophil infiltration; meningeal, perivascular and intracerebral neutrophil influx was scored on a scale 0–4, means of 16 brain slides per mouse in the coronal plane are displayed (WT, n = 11; Asc−/−, n = 8; Nlrp3−/−, n = 9; G). Sum of intracerebral hemorrhages and subpial hemorrhages per mouse (WT, n = 11; Asc−/−; n = 8; Nlrp3−/−; n = 9; H).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Histopathology in Asc−/−, Nlrp3−/−, and WT mice with pneumococcal meningitis. Representative brain slides showing neutrophil infiltration in the meninges 30 hours after induction of pneumococcal meningitis in a WT mouse (A), Asc−/− mouse (B) and Nlrp3−/− mouse (C). Perivascular cuffing 30 hours after induction of pneumococcal meningitis in a WT mouse (D), Asc−/− mouse (E) and Nlrp3−/− mouse (F), showing frequent intracerebral and subpial hemorrhages associated with neutrophil infiltration; meningeal, perivascular and intracerebral neutrophil influx was scored on a scale 0–4, means of 16 brain slides per mouse in the coronal plane are displayed (WT, n = 11; Asc−/−, n = 8; Nlrp3−/−, n = 9; G). Sum of intracerebral hemorrhages and subpial hemorrhages per mouse (WT, n = 11; Asc−/−; n = 8; Nlrp3−/−; n = 9; H).
Mentions: Neutrophil infiltrate in the brain was more pronounced in Nlrp3−/− mice at 30 h after inoculation as compared to WT mice (median score 1.5 versus 2.4, p=0.018; Figure 5G). Nlrp3−/− mice also showed an elevated number of intracerebral and subpial hemorrhages and as compared to WT mice (median 12.5 versus 1.0 per slide, p=0.02; Figure 5H). Asc−/− mice showed no difference in neutrophil influx score and intracerebral hemorrhages compared to WT mice. Brain MPO levels were similar in both knockouts and wild-type mice (data not shown).

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