<i>NLRP1</i>
            haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

Levandowski, Cecilia B.; Mailloux, Christina M.; Ferrara, Tracey M.; Gowan, Katherine; Ben, Songtao; Jin, Ying; McFann, Kimberly K.; Holland, Paulene J.; Fain, Pamela R.; Dinarello, Charles A.; Spritz, Richard A.

doi:10.1073/pnas.1222808110

Cited by 196 publications

(144 citation statements)

References 31 publications

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“…In the absence of ATP, macrophages stimulated with LPS synthesize large quantities of the IL-1β precursor but only process and release less than 20% of the mature cytokine into cell culture supernatants (22,23). Here, we show that ATP also induces the secretion of mature IL-37 from RAW-IL-37 cells and PBMCs.…”

Section: Nuclear Translocation and Anti-inflammatory Function Of Il-37mentioning

confidence: 63%

Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

Bulau

Nold²,

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37-mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrowderived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck-like protein containing a carboxyl-terminal caspase recruitment domain-and NLRP3-deficient cells does not reduce levels of IL-6 and IL-1β upon LPS stimulation. IL-37-expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL-37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37-neutralizing antibodies before LPS challenge. In IL-37-expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual-function cytokine with intra-and extracellular properties for suppressing innate inflammation. W ith the exception of the IL-1 receptor antagonist, members of the IL-1 family are first synthesized as precursor molecules containing a propeptide domain lacking a classical signal sequence (1). Caspase-1 has emerged as the main intracellular processing enzyme responsible for maturation of active IL-1β and IL-18, which are then released into the extracellular space, as shown for IL-1β and IL-18 (2, 3). The IL-1 family member IL-37 is also synthesized as a precursor and is processed to its mature form upon LPS treatment (4, 5). Caspase-1 seems to be the main enzyme responsible for the in vitro maturation of IL-37 in comparison to caspase-4 and granzyme B (4). A putative cleavage site for caspase-1 is located in exon 1 between residues D20 and E21 of IL-37 (4). HEK 293 or CHO cells transfected with the IL-37 precursor release IL-37 starting at amino acid V46, suggesting a second cleavage site in the sequence encoded by exon 2 (6). We previously demonstrated that processing of IL-37 is only partially inhibited by caspase-1 inhibitors, indicating that caspase-1 is not the only enzyme responsible for the processing of IL-37 (5)...

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Section: Nuclear Translocation and Anti-inflammatory Function Of Il-37mentioning

confidence: 63%

Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

Bulau

Nold²,

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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185

231

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“…Microbial stimulation of PBMCs from healthy subjects carrying the high-risk haplotype consistently resulted in increased production of IFN-γ and IL-1β, both of which have been implicated in the pathogenesis of several autoimmune diseases, including vitiligo (27)(28)(29). Further studies are needed to evaluate whether IL-1 blocking agents, which are used in the treatment of a broad spectrum of conditions characterized by IL-1-mediated inflammation (29), could represent a useful treatment approach to vitiligo.…”

Section: Discussionmentioning

confidence: 99%

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cavalli

Hayashi

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genomewide association study of 2,853 Caucasian vitiligo patients. The superenhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5-and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.A utoimmune diseases are a group of over 80 disorders that together affect 3-5% of the United States population (1, 2). Many autoimmune diseases are associated with genetic variation in the HLA class I and class II gene regions of the major histocompatibility complex (MHC) on chromosome 6p21.3. HLA class I molecules present peptide antigens on the surface of almost all cells, whereas HLA class II molecules present antigens on the surface of antigen-presenting cells, such as dendritic cells, mononuclear phagocytes, and B cells. Contributions of HLA molecules to autoimmunity have almost exclusively focused on antigenic diversity and specificity. Although polymorphisms in intergenic regions of the MHC might additionally affect the complex transcriptional regulation of HLA genes, the potential role of these noncoding regions in the pathogenesis of autoimmune diseases has received much less attention.Vitiligo is an autoimmune disease in which white spots of skin and overlying hair result from progressive destruction of melanocytes by autoreactive T cells (3). In previous genome-wide association studies of autoimmune vitiligo in European-derived Caucasian (EUR) populations, we have identified association with 27 different loci (4-6), most strongly with MHC class II r...

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“…From previous studies (35,36), in freshly obtained human PBMCs, ϳ10 -15% of the total intracellular content of the IL-1␤ precursor is processed by caspase-1 and secreted during a 24-h culture of monocytes, whereas most of the precursor remains unprocessed in the cells. This was also observed in the present study.…”

Section: A Comparison Of the Effect Of Itf2357 With That Of Its Analomentioning

confidence: 97%

Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in Vivo

Fossati

Marchetti

et al. 2015

Journal of Biological Chemistry

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Background: Low concentrations of HDAC inhibitors suppress inflammation, but HDAC inhibitors are toxic at higher concentrations. Results: ITF3056 specifically inhibits HDAC8 activity and reduces proinflammatory cytokine production from human blood monocytes and in vivo but lacks cell toxicity. Conclusion: Specific inhibition of HDAC8 reduces inflammation with low cell toxicity. Significance: Inhibition of specific HDACs is preferred for treating inflammatory diseases, with fewer side effects.

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NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome

Cited by 196 publications

References 31 publications

Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in Vivo

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