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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways

Authors: Ya-feng Li, Gayani Nanayakkara, Yu Sun, Xinyuan Li, Luqiao Wang, Ramon Cueto, Ying Shao, Hangfei Fu, Candice Johnson, Jiali Cheng, Xiongwen Chen, Wenhui Hu, Jun Yu, Eric T. Choi, Hong Wang, Xiao-feng Yang

Published in: Journal of Hematology & Oncology | Issue 1/2017

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Abstract

Background

It is well established that caspase-1 exerts its biological activities through its downstream targets such as IL-1β, IL-18, and Sirt-1. The microarray datasets derived from various caspase-1 knockout tissues indicated that caspase-1 can significantly impact the transcriptome. However, it is not known whether all the effects exerted by caspase-1 on transcriptome are mediated only by its well-known substrates. Therefore, we hypothesized that the effects of caspase-1 on transcriptome may be partially independent from IL-1β, IL-18, and Sirt-1.

Methods

To determine new global and tissue-specific gene regulatory effects of caspase-1, we took novel microarray data analysis approaches including Venn analysis, cooperation analysis, and meta-analysis methods. We used these statistical methods to integrate different microarray datasets conducted on different caspase-1 knockout tissues and datasets where caspase-1 downstream targets were manipulated.

Results

We made the following important findings: (1) Caspase-1 exerts its regulatory effects on the majority of genes in a tissue-specific manner; (2) Caspase-1 regulatory genes partially cooperates with genes regulated by sirtuin-1 during organ injury and inflammation in adipose tissue but not in the liver; (3) Caspase-1 cooperates with IL-1β in regulating less than half of the genes involved in cardiovascular disease, organismal injury, and cancer in mouse liver; (4) The meta-analysis identifies 40 caspase-1 globally regulated genes across tissues, suggesting that caspase-1 globally regulates many novel pathways; and (5) The meta-analysis identified new cooperatively and non-cooperatively regulated genes in caspase-1, IL-1β, IL-18, and Sirt-1 pathways.

Conclusions

Our findings suggest that caspase-1 regulates many new signaling pathways potentially via its known substrates and also via transcription factors and other proteins that are yet to be identified.
Appendix
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Literature
1.
2.
3.
Chalkiadaki A, Guarente L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 2012;16(2):180–8.CrossRefPubMedPubMedCentral
4.
Xi H, Zhang Y, Xu Y, Yang WY, Jiang X, Sha X, et al. Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ Res. 2016;118(10):1525–39.CrossRefPubMed
5.
Van Diepen JA, Stienstra R, Vroegrijk IO, van den Berg SA, Salvatori D, Hooiveld GJ, et al. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J Lipid Res. 2013;54(2):448–56.CrossRefPubMedPubMedCentral
6.
Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108(37):15324–9.CrossRefPubMedPubMedCentral
7.
Yin Y, Pastrana JL, Li X, Huang X, Mallilankaraman K, Choi ET, et al. Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci. 2013;18:638–49.CrossRef
8.
Yin Y, Yan Y, Jiang X, Mai J, Chen NC, Wang H, et al. Inflammasomes are differentially expressed in cardiovascular and other tissues. Int J Immunopathol Pharmacol. 2009;22(2):311–22.CrossRefPubMedPubMedCentral
9.
Shen J, Yin Y, Mai J, Xiong X, Pansuria M, Liu J, et al. Caspase-1 recognizes extended cleavage sites in its natural substrates. Atherosclerosis. 2010;210(2):422–9.CrossRefPubMed
10.
Shao Y, Cheng Z, Li X, Chernaya V, Wang H, Yang XF. Immunosuppressive/anti-inflammatory cytokines directly and indirectly inhibit endothelial dysfunction—a novel mechanism for maintaining vascular function. J Hematol Oncol. 2014;7(1):80.CrossRefPubMedPubMedCentral
11.
Yin Y, Li X, Sha X, Xi H, Li YF, Shao Y, et al. Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. Arterioscler Thromb Vasc Biol. 2015;35(4):804–16.CrossRefPubMedPubMedCentral
12.
Lopez-Pastrana J, Ferrer L, Li YF, Xiong X, Xi H, Cueto R, et al. Inhibition of caspase-1 activation in endothelial cells improves angiogenesis—a novel therapeutic potential for ischemia. J Biol Chem. 2015;290(28):17485–94.CrossRefPubMedPubMedCentral
13.
Li YF, Ren LN, Guo G, Cannella LA, Chernaya V, Samuel S, et al. Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy. J Hematol Oncol. 2015;8(1):33.CrossRefPubMedPubMedCentral
14.
Li Y-F, Huang X, Li X, Gong R, Yin Y, Nelson J, et al. Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair. Frontiers in Bioscience (Landmark Edition). 2016;21(January):178–91.
15.
Ferrer LM, Monroy AM, Lopez-Pastrana J, Nanayakkara G, Cueto R, Li YF, et al. Caspase-1 plays a critical role in accelerating chronic kidney disease-promoted neointimal hyperplasia in the carotid artery. J Cardiovasc Transl Res. 2016;9(2):135–44.CrossRefPubMedPubMedCentral
16.
17.
Gastaldello S, Chen X, Callegari S, Masucci MG. Caspase-1 promotes Epstein-Barr virus replication by targeting the large tegument protein deneddylase to the nucleus of productively infected cells. PLoS Pathog. 2013;9(10):e1003664.CrossRefPubMedPubMedCentral
18.
Aries A, Whitcomb J, Shao W, Komati H, Saleh M, Nemer M. Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate. Cell Death Dis. 2014;5:e1566.CrossRefPubMedPubMedCentral
19.
He F, Doucet JA, Stephens JM. Caspase-mediated degradation of PPARgamma proteins in adipocytes. Obesity (Silver Spring). 2008;16(8):1735–41.CrossRef
20.
Bruchard M, Rebe C, Derangere V, Togbe D, Ryffel B, Boidot R, et al. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat Immunol. 2015;16(8):859–70.CrossRefPubMed
21.
Mao PL, Jiang Y, Wee BY, Porter AG. Activation of caspase-1 in the nucleus requires nuclear translocation of pro-caspase-1 mediated by its prodomain. J Biol Chem. 1998;273(37):23621–4.CrossRefPubMed
22.
Fankhauser C, Friedlander RM, Gagliardini V. Prevention of nuclear localization of activated caspases correlates with inhibition of apoptosis. Apoptosis. 2000;5(2):117–32.CrossRefPubMed
23.
24.
Arasappan D, Tong W, Mummaneni P, Fang H, Amur S. Meta-analysis of microarray data using a pathway-based approach identifies a 37-gene expression signature for systemic lupus erythematosus in human peripheral blood mononuclear cells. BMC Med. 2011;9:65.CrossRefPubMedPubMedCentral
25.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.CrossRefPubMedPubMedCentral
26.
27.
28.
Ritchie ME, Phipson B, Wu D, Hu YF, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research. 2015;43(7).
29.
30.
Benjamini Y, Hochberg Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Royal Stat Soc Series B-Methodological. 1995;57(1):289–300.
31.
Marot G, Foulley JL, Mayer CD, Jaffrezic F. Moderated effect size and P-value combinations for microarray meta-analyses. Bioinformatics. 2009;25(20):2692–9.CrossRefPubMed
32.
Schwarzer G, Carpenter JR, Rücker G. Meta-analysis with R. Switzerland: Springer; 2015.
33.
Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486(7404):549–53.PubMedPubMedCentral
34.
35.
Kotas ME, Jurczak MJ, Annicelli C, Gillum MP, Cline GW, Shulman GI, et al. Role of caspase-1 in regulation of triglyceride metabolism. Proc Natl Acad Sci U S A. 2013;110(12):4810–5.CrossRefPubMedPubMedCentral
36.
Sun Q, Gao W, Loughran P, Shapiro R, Fan J, Billiar TR, et al. Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress. J Biol Chem. 2013;288(22):15947–58.CrossRefPubMedPubMedCentral
37.
Skeldon AM, Faraj M, Saleh M. Caspases and inflammasomes in metabolic inflammation. Immunol Cell Biol. 2014;92(4):304–13.CrossRefPubMed
38.
39.
Gaudet RG, Sintsova A, Buckwalter CM, Leung N, Cochrane A, Li J, et al. INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity. Science. 2015;348(6240):1251–5.CrossRefPubMed
40.
Ding N, Zhang Y, Loughran PA, Wang Q, Tsung A, Billiar TR. TIFA upregulation after hypoxia-reoxygenation is TLR4- and MyD88-dependent and associated with HMGB1 upregulation and release. Free Radic Biol Med. 2013;63:361–7.CrossRefPubMedPubMedCentral
41.
Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011;43(9):887–92.CrossRefPubMedPubMedCentral
42.
Heiker JT, Kern M, Kosacka J, Flehmig G, Stumvoll M, Shang E, et al. Nicotinamide nucleotide transhydrogenase mRNA expression is related to human obesity. Obesity (Silver Spring). 2013;21(3):529–34.CrossRef
43.
Sheeran FL, Rydstrom J, Shakhparonov MI, Pestov NB, Pepe S. Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium. Biochim Biophys Acta. 2010;1797(6–7):1138–48.CrossRefPubMed
44.
Preisler N, Orngreen MC, Echaniz-Laguna A, Laforet P, Lonsdorfer-Wolf E, Doutreleau S, et al. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? Neurology. 2012;78(4):265–8.CrossRefPubMed
45.
Wuyts W, Reyniers E, Ceuterick C, Storm K, de Barsy T, Martin JJ. Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene. Am J Med Genet A. 2005;133A(1):82–4.CrossRefPubMed
46.
47.
48.
Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, et al. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A. 2014;111(43):15514–9.CrossRefPubMedPubMedCentral
49.
Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, van den Berg SA, et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 2010;12(6):593–605.CrossRefPubMedPubMedCentral
50.
Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155(6):1282–95.CrossRefPubMedPubMedCentral
51.
52.
Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med. 1999;18(3):321–59.CrossRefPubMed
53.
Quante M, Bhagat G, Abrams JA, Marache F, Good P, Lee MD, et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell. 2012;21(1):36–51.CrossRefPubMedPubMedCentral
54.
Wang IM, Zhang B, Yang X, Zhu J, Stepaniants S, Zhang C, et al. Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers. Mol Syst Biol. 2012;8:594.CrossRefPubMedPubMedCentral
55.
Sparna T, Retey J, Schmich K, Albrecht U, Naumann K, Gretz N, et al. Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes. BMC Genomics. 2010;11:226.CrossRefPubMedPubMedCentral
56.
Ehlers M, Papewalis C, Stenzel W, Jacobs B, Meyer KL, Deenen R, et al. Immunoregulatory natural killer cells suppress autoimmunity by down-regulating antigen-specific CD8+ T cells in mice. Endocrinology. 2012;153(9):4367–79.CrossRefPubMed
57.
Knodler LA, Crowley SM, Sham HP, Yang H, Wrande M, Ma C, et al. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 2014;16(2):249–56.CrossRefPubMedPubMedCentral
58.
Mercken EM, Hu J, Krzysik-Walker S, Wei M, Li Y, McBurney MW, et al. SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell. 2014;13(1):193–6.CrossRefPubMed
59.
Purushotham A, Xu Q, Li X. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J. 2012;26(2):656–67.CrossRefPubMedPubMedCentral
60.
Libert S, Pointer K, Bell EL, Das A, Cohen DE, Asara JM, et al. SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell. 2011;147(7):1459–72.CrossRefPubMedPubMedCentral
61.
Beier UH, Wang L, Han R, Akimova T, Liu Y, Hancock WW. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal. 2012;5(229):ra45.CrossRefPubMedPubMedCentral
62.
Oka S, Alcendor R, Zhai P, Park JY, Shao D, Cho JY, et al. PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011;14(5):598–611.CrossRefPubMedPubMedCentral
63.
Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu XT, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007;100(10):1512–21.CrossRefPubMed
64.
65.
Merkle S, Frantz S, Schon MP, Bauersachs J, Buitrago M, Frost RJ, et al. A role for caspase-1 in heart failure. Circ Res. 2007;100(5):645–53.CrossRefPubMed
66.
67.
68.
69.
Wang M, Zhao XM, Tan H, Akutsu T, Whisstock JC, Song J. Cascleave 2.0, a new approach for predicting caspase and granzyme cleavage targets. Bioinformatics. 2014;30(1):71–80.CrossRefPubMed
70.
Bulau AM, Nold MF, Li S, Nold-Petry CA, Fink M, Mansell A, et al. Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. Proc Natl Acad Sci U S A. 2014;111(7):2650–5.CrossRefPubMedPubMedCentral
71.
Weigert A, Cremer S, Schmidt MV, von Knethen A, Angioni C, Geisslinger G, et al. Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood. 2010;115(17):3531–40.CrossRefPubMed
72.
Ulrichts P, Bovijn C, Lievens S, Beyaert R, Tavernier J, Peelman F. Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site. J Cell Sci. 2010;123(Pt 2):256–65.CrossRefPubMed
73.
Kim MJ, Yoo JY. Active caspase-1-mediated secretion of retinoic acid inducible gene-I. J Immunol. 2008;181(10):7324–31.CrossRefPubMed
74.
75.
Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe. 2011;9(5):363–75.CrossRefPubMedPubMedCentral
76.
Wang L, Fu H, Nanayakkara G, Li Y, Shao Y, Johnson C, Cheng J, et al. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. J Hematol Oncol. 2016;9(1):122.CrossRefPubMedPubMedCentral
77.
Becker CE, Creagh EM, O'Neill LA. Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1beta secretion. J Biol Chem. 2009;284(50):34531–7.CrossRefPubMedPubMedCentral
78.
Keller M, Ruegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008;132(5):818–31.CrossRefPubMed
79.
Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, Compan V, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 2014;15(8):738–48.CrossRefPubMed
80.
Mitra S, Wewers MD, Sarkar A. Mononuclear phagocyte-derived microparticulate caspase-1 induces pulmonary vascular endothelial cell injury. PLoS One. 2015;10(12):e0145607.CrossRefPubMedPubMedCentral
81.
Brown GT, McIntyre TM. Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1beta-rich microparticles. J Immunol. 2011;186(9):5489–96.CrossRefPubMedPubMedCentral
Metadata
Title
Analyses of caspase-1-regulated transcriptomes in various tissues lead to identification of novel IL-1β-, IL-18- and sirtuin-1-independent pathways
Authors
Ya-feng Li
Gayani Nanayakkara
Yu Sun
Xinyuan Li
Luqiao Wang
Ramon Cueto
Ying Shao
Hangfei Fu
Candice Johnson
Jiali Cheng
Xiongwen Chen
Wenhui Hu
Jun Yu
Eric T. Choi
Hong Wang
Xiao-feng Yang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0406-2

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