Editors' ChoiceImmunology

NLRP3: From inflammasome to nucleus

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Science Signaling  04 Aug 2015:
Vol. 8, Issue 388, pp. ec211
DOI: 10.1126/scisignal.aad1392

In innate immune cells, such as macrophages, the cytosolic receptor NLRP3 senses endogenous danger-associated molecular patterns and pathogen-associated molecules to stimulate an inflammatory response. Upon binding ligand, NLRP3 forms a complex with the adaptor protein ASC and the protease caspase-1, leading to caspase-1 activation and the processing of the precursor forms of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Bruchard et al. showed that the abundance of Nlrp3 mRNA was increased in naïve mouse CD4+ T cells upon stimulation through the T cell receptor. Immunofluorescence analysis showed that, in naïve CD4+ T cells that were differentiated in vitro to generate T helper 1 (TH1) cells, NLRP3 was cytosolic; however, in differentiated TH2 cells, NLRP3 was localized to the nucleus. Compared with wild-type TH2 cells, Nlrp3–/– TH2 cells produced less IL-4 and other TH2-type cytokines; however, TH2 cells derived from mice deficient in either ASC or caspase-1 exhibited normal differentiation and cytokine production. Analysis of TH2 cells by chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-seq) showed that NLRP3 bound to DNA, including promoter and enhancer regions. Binding of NLRP3 to the Il4 promoter required the transcription factor interferon regulatory factor 4 (IRF4), and coimmunoprecipitation studies showed that NLRP3 bound to IRF4. Luciferase reporter assays with the Il4 promoter indicated that both NLRP3 and IRF4 were required for optimal Il4 expression. In two mouse models (allergic asthma and B16F10 melanoma tumor formation) in which TH2 cells are thought to exacerbate disease, TH2 cells from Nlrp3–/– mice produced less IL-4 than did their wild-type counterparts, and the knockout mice exhibited less disease progression, suggesting that targeting the NRLP3-IRF4 interaction might provide therapeutic benefit. As Ting and Harton discuss in commentary, these results suggest a transcriptional regulatory role for an inflammasome protein in cells of the adaptive immune system, raising the possibility that other NLRs may have functions outside of innate immune cells.

M. Bruchard, C. Rebé, V. Derangère, D. Togbé, B. Ryffel, R. Boidot, E. Humblin, A. Hamman, F. Chalmin, H. Berger, A. Chevriaux, E. Limagne, L. Apetoh, F. Végran, F. Ghiringhelli, The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat. Immunol. 16, 859–870 (2015). [PubMed]

J. P. Y. Ting, J. A. Harton, NLRP3 moonlights in TH2 polarization. Nat. Immunol. 16, 794–796 (2015). [PubMed]