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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
The NLRP3 inflammasome is involved with the pathogenesis of Mayaro virus
Luiza A de Castro-Jorge1, Renan V H de Carvalho1, Taline M Klein2
1Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo. Ribeirão Preto, Brazil.
Abstract:
Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3-/-, Aim2-/-, Asc-/-and Casp1/11-/-mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1β. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1β and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.
Insights
Mayaro virus (MAYV) infection triggers the NLRP3 inflammasome, a key driver of inflammation and disease symptoms. This inflammasome activation is crucial for Mayaro fever pathogenesis in both cellular models and infected patients.
Area of Science:
- Immunology
- Virology
- Pathogenesis
Background:
- Mayaro virus (MAYV) is an emerging arbovirus causing Mayaro fever, a severe inflammatory disease.
- MAYV infection presents with fever, rash, and prolonged arthralgia, posing a public health concern.
- The pathogenesis and immune response to MAYV are poorly understood compared to other arboviruses.
Purpose of the Study:
- To investigate the role of inflammasomes in Mayaro virus pathogenesis.
- To elucidate the mechanisms of NLRP3 inflammasome activation by MAYV.
- To assess the therapeutic potential of targeting the NLRP3 inflammasome in MAYV infection.
Main Methods:
- Established MAYV infection models in bone marrow-derived macrophages and mice.
- Utilized inflammasome-deficient (Nlrp3-/-, Aim2-/-, Asc-/-, Casp1/11-/-) mice for infection studies.
- Measured cytokine production (IL-1β, IL-18) and inflammasome protein expression (NLRP3, ASC, AIM2, Caspase-1).
- Assessed ROS production and potassium efflux in MAYV-infected macrophages.
- Analyzed serum from MAYV-infected patients for inflammasome markers.
Main Results:
- MAYV replicates in macrophages and induces inflammasome protein expression.
- NLRP3 inflammasome, not AIM2, is essential for IL-1β production in MAYV-infected macrophages.
- MAYV activates NLRP3 inflammasome via reactive oxygen species (ROS) and potassium efflux.
- NLRP3 inflammasome deficiency in mice reduces footpad swelling, inflammation, and pain.
- Elevated caspase-1, IL-1β, and IL-18 levels were detected in MAYV-infected patients.
Conclusions:
- The NLRP3 inflammasome plays a critical role in Mayaro virus pathogenesis.
- NLRP3 inflammasome activation contributes to the inflammatory symptoms of Mayaro fever.
- Targeting the NLRP3 inflammasome could be a therapeutic strategy for MAYV infections.
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