Abstract
Missense mutations of the gene encoding NLRP3 are associated with autoinflammatory disorders characterized with excessive production of interleukin-1beta (IL-1beta). Here we analyzed the immune responses of gene-targeted mice carrying a mutation in the Nlrp3 gene equivalent to the human mutation associated with Muckle-Wells Syndrome. We found that antigen-presenting cells (APCs) from such mice produced massive amounts of IL-1beta upon stimulation with microbial stimuli in the absence of ATP. This was likely due to a diminished inflammasome activation threshold that allowed a response to the small amount of agonist. Moreover, the Nlrp3 gene-targeted mice exhibited skin inflammation characterized by neutrophil infiltration and a Th17 cytokine-dominant response, which originated from hematopoietic cells. The inflammation of Nlrp3 gene-targeted mice resulted from excess IL-1beta production from APCs, which augmented Th17 cell differentiation. These results demonstrate that the NLRP3 mutation leads to inflammasome hyperactivation and consequently Th17 cell-dominant immunopathology in autoinflammation.
MeSH terms
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Adenosine Triphosphate / immunology
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Adenosine Triphosphate / metabolism
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Animals
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism*
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Cell Differentiation / immunology
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Cytokines / immunology
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Cytokines / metabolism
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Inflammation / genetics*
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Inflammation / immunology
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Interleukin-18 / biosynthesis
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Interleukin-18 / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology*
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mutation / genetics
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Mutation / immunology
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NLR Family, Pyrin Domain-Containing 3 Protein
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Skin / immunology
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Skin / metabolism
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Skin / pathology
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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Carrier Proteins
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Cytokines
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Interleukin-18
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Receptors, Antigen, T-Cell
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Adenosine Triphosphate