Abstract
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Asthma / genetics
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Asthma / immunology
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Asthma / metabolism
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Blotting, Western
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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 / genetics
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Cell Differentiation / immunology*
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Cell Line, Tumor
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / immunology
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Inflammasomes / genetics
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Inflammasomes / immunology
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Inflammasomes / metabolism
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / immunology
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Interferon Regulatory Factors / metabolism
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Interleukin-4 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NIH 3T3 Cells
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NLR Family, Pyrin Domain-Containing 3 Protein
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / metabolism
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Protein Binding / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / immunology
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Trans-Activators / genetics
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Trans-Activators / immunology*
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Trans-Activators / metabolism
Substances
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Carrier Proteins
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Inflammasomes
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Interferon Regulatory Factors
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Trans-Activators
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interferon regulatory factor-4
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Interleukin-4
Associated data
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GEO/GSE54561
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GEO/GSE64749