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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
Published on: May 22, 2014
Critical roles of NLRP3 inflammasome in IL-1β secretion induced by Corynebacterium pseudotuberculosis in vitro
Zuoyong Zhou1, Hexian Li2, Shangquan Tian2
1College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China; Veterinary Science Engineering Research Center of Chongqing, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
Abstract:
Corynebacterium pseudotuberculosis is a prominent human and animal pathogen causing chronic inflammatory diseases. Interleukin-1β (IL-1β) is involved in the response to such pathogenic infections. However, the mechanism by which IL-1β is secreted during C. pseudotuberculosis infection remains unclear. This study aimed to investigate the mechanism underlying IL-1β secretion by macrophages infected with C. pseudotuberculosis. Herein, we firstly revealed that nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 (Casp1) play critical roles in IL-1β secretion rather than IL-1β precursor (pro-IL-1β) expression in C. pseudotuberculosis-infected macrophages. Toll like receptor 4 (TLR4) is partially involved in IL-1β secretion, while absent in melanoma 2 (AIM2) is not involved in IL-1β secretion by C. pseudotuberculosis-infected macrophages. In addition, nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinases (p38 MAPK) inhibitors almost attenuated IL-1β secretion, implying that NF-κB and p38MAPK pathway are involved in IL-1β secretion in C. pseudotuberculosis-infected macrophages. Furthermore, C. pseudotuberculosis were significantly more numerous in Nlrp3-/-, Asc-/-, and Casp-1-/- macrophages than in WT macrophages at 24 h after infection (P < 0.05), indicating that NLRP3 inflammasome components limit C. pseudotuberculosis replication in macrophages. Together, these data provide novel insights into the mechanisms underlying IL-1β secretion in C. pseudotuberculosis-infected macrophages and further the current understanding of the host pro-inflammatory immune response against this pathogen.
Insights
The NLRP3 inflammasome, including ASC and Caspase-1, is crucial for secreting Interleukin-1β (IL-1β) during Corynebacterium pseudotuberculosis infection. This pathway also helps control bacterial growth within macrophages.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Corynebacterium pseudotuberculosis is a significant pathogen in humans and animals, causing persistent inflammatory conditions.
- Interleukin-1β (IL-1β) is a key mediator in the host response to bacterial infections, but its secretion mechanism during C. pseudotuberculosis infection is not fully understood.
- Understanding IL-1β secretion pathways is vital for developing strategies against C. pseudotuberculosis-induced inflammation.
Purpose of the Study:
- To elucidate the molecular mechanisms governing IL-1β secretion by macrophages in response to C. pseudotuberculosis infection.
- To investigate the roles of specific inflammasome components (NLRP3, ASC, Caspase-1, AIM2) and signaling pathways (TLR4, NF-κB, p38 MAPK) in this process.
Main Methods:
- Macrophage infection models with C. pseudotuberculosis.
- Analysis of IL-1β and pro-IL-1β expression levels.
- Use of knockout macrophages (Nlrp3-/-, Asc-/-, Casp-1-/-) and pharmacological inhibitors (NF-κB, p38 MAPK).
- Bacterial load quantification in infected macrophages.
Main Results:
- NLRP3, ASC, and Caspase-1 are essential for IL-1β secretion, not pro-IL-1β expression, in C. pseudotuberculosis-infected macrophages.
- Toll-like receptor 4 (TLR4) partially contributes to IL-1β secretion, while Absent in melanoma 2 (AIM2) is not involved.
- NF-κB and p38 MAPK signaling pathways significantly influence IL-1β secretion.
- NLRP3 inflammasome components restrict C. pseudotuberculosis replication within macrophages.
Conclusions:
- The NLRP3 inflammasome pathway is a critical regulator of IL-1β secretion during C. pseudotuberculosis infection.
- NF-κB and p38 MAPK signaling pathways are involved in the IL-1β secretion process.
- The NLRP3 inflammasome plays a dual role in host defense by mediating inflammation and controlling bacterial proliferation.
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