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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Activation of the NLRP3 inflammasome by group B streptococci
Alessandro Costa1, Rahul Gupta, Giacomo Signorino
1Elie Metchnikoff Department, University of Messina, Messina I-98125, Italy.
Abstract:
Group B Streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show in this study that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1β and IL-18. IL-1β release required both pro-IL-1β transcription and caspase-1-dependent proteolytic cleavage of intracellular pro-IL-1β. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1β mRNA in response to GBS. Pro-IL-1β cleavage and secretion of the mature IL-1β form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of β-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, apoptosis-associated speck-like protein, or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.
Insights
Group B Streptococcus (GBS) infections trigger the NLRP3 inflammasome, a key immune defense. This inflammasome activation is crucial for controlling GBS and requires a bacterial toxin, enhancing host resistance.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Group B Streptococcus (GBS) causes severe infections like sepsis and meningitis in vulnerable populations.
- The inflammasome, an inflammatory signaling complex, plays a role in host defense, but its involvement in GBS infection is unclear.
Purpose of the Study:
- To investigate the role of inflammasome activation in host defense against Group B Streptococcus.
- To elucidate the specific inflammasome components and bacterial factors involved in the immune response to GBS.
Main Methods:
- Utilized murine bone marrow-derived conventional dendritic cells to study GBS-induced immune responses.
- Assessed the production of IL-1β and IL-18, and the requirement for TLR adaptors (MyD88, TLR2), caspase-1, NLRP3, and ASC.
- Investigated the necessity of GBS β-hemolysin for inflammasome activation.
- Compared the susceptibility of wild-type mice and knockout mice (NLRP3, ASC, caspase-1) to GBS infection.
Main Results:
- Dendritic cells produced IL-1β and IL-18 in response to GBS.
- IL-1β secretion depended on pro-IL-1β transcription (via MyD88) and caspase-1 cleavage.
- NLRP3 inflammasome activation, involving NLRP3 and ASC, was essential for IL-1β processing and secretion.
- GBS β-hemolysin was required for NLRP3 inflammasome activation.
- Mice deficient in NLRP3, ASC, or caspase-1 exhibited increased susceptibility to GBS infection.
Conclusions:
- The NLRP3 inflammasome is a critical component of the host immune response against Group B Streptococcus.
- Activation of the NLRP3 inflammasome is linked to GBS β-hemolysin production, highlighting a key bacterial virulence factor.
- Targeting the NLRP3 inflammasome pathway could represent a therapeutic strategy for GBS infections.
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