Human parvovirus B19 nonstructural protein NS1 activates NLRP3 inflammasome signaling in adult‑onset Still's disease

Chen,Der‑Yuan; Chen,Yi‑Ming; Chen,Hsin‑Hua; Hsieh,Chia‑Wei; Gung,Ning‑Rong; Hung,Wei‑Ting; Tzang,Bor‑Show; Hsu,Tsai‑Ching

doi:10.3892/mmr.2017.8275

Human parvovirus B19 nonstructural protein NS1 activates NLRP3 inflammasome signaling in adult‑onset Still's disease

Authors:
- Der‑Yuan Chen
- Yi‑Ming Chen
- Hsin‑Hua Chen
- Chia‑Wei Hsieh
- Ning‑Rong Gung
- Wei‑Ting Hung
- Bor‑Show Tzang
- Tsai‑Ching Hsu
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Affiliations: Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan, R.O.C., Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
Published online on: December 12, 2017 https://doi.org/10.3892/mmr.2017.8275
Pages: 3364-3371

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Abstract

Dysregulation of inflammasomes serves a pathogenic role in autoinflammatory diseases (AIDs) and adult-onset Still's disease (AOSD) has been categorized as an AID. The present study investigated the expression of NLR family pyrin domain containing proteins (NLRPs) inflammasome in patients with AOSD, the effect of inflammasome inhibitors on NLRP3 signaling and whether human parvovirus B19‑associated antigens can activate NLRP3 in patients with AOSD. mRNA expression levels of NLRPs in peripheral blood mononuclear cells (PBMCs) from 34 patients with AOSD and 14 healthy individuals were determined using reverse transcription‑quantitative polymerase chain reaction. Protein expression of NLRP3 was evaluated by western blotting. Supernatant cytokine levels were measured by ELISA. Among the NLRPs investigated in the present study, NLRP3 transcripts were markedly elevated and expression of NLRP2, NLRP7 and NLRP12 was decreased in patients with AOSD compared with the controls. Treatment with NLRP3 inhibitors significantly reduced downstream NLRP3 signaling in PBMCs form patients with AOSD. B19‑nonstructural protein (NS)1 stimulation of PBMCs from patients with AOSD induced significant upregulation of transcript levels of NLRP3, caspase‑1 and interleukin (IL)‑1β compared with PBMCs from healthy controls. B19‑NS1 stimulation of PBMCs from patients with AOSD induced significant increase in supernatant levels of IL‑1β and protein expression of NLRP3, caspase‑1, IL‑1β, and IL‑18 compared with healthy controls. Elevated expression of NLRP3 and its downstream inflammasome signaling components in patients with AOSD indicated a potential pathogenic role of B19‑NS1. Thus, B19‑NS1 may induce expression of IL‑1β and IL‑18 through activation of caspase‑1‑associated NLRP3‑inflammasome in AOSD.

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1	Muruve DA, Pétrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, Parks RJ and Tschopp J: The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 452:103–107. 2008. View Article : Google Scholar : PubMed/NCBI
2	Martinon F, Gaide O, Pétrilli V, Mayor A and Tschopp J: NALP inflammasome: A central role in innate immunity. Semin Immunopathol. 29:213–229. 2007. View Article : Google Scholar : PubMed/NCBI
3	Schroder K and Tschopp J: The inflammasomes. Cell. 140:821–832. 2010. View Article : Google Scholar : PubMed/NCBI
4	Tschopp J, Martinon F and Burns K: NALPs: A novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 4:95–104. 2003. View Article : Google Scholar : PubMed/NCBI
5	Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, et al: The NLR gene family: A standard nomenclature. Immunity. 28:285–287. 2008. View Article : Google Scholar : PubMed/NCBI
6	Sidiropoulos PI, Goulielmos G, Voloudakis GK, Petraki E and Boumpas DT: Inflammasomes and rheumatic diseases: Evolving concepts. Ann Rheum Dis. 67:1382–1389. 2008. View Article : Google Scholar : PubMed/NCBI
7	Busso N and So A: Microcrystals as DAMPs and their role in joint inflammation. Rheumatology (Oxford). 51:1154–1160. 2012. View Article : Google Scholar : PubMed/NCBI
8	Varghese GP, Uporova L, Halfvarson J, Sirsjö A and Fransén K: Polymorphism in the NLRP3 inflammasome-associated EIF2K2 gene and inflammatory bowel disease. Mol Med Rep. 11:4579–4584. 2015. View Article : Google Scholar : PubMed/NCBI
9	McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T, et al: Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 97:133–144. 1999. View Article : Google Scholar : PubMed/NCBI
10	Masters SL, Simon A, Aksentijevich I and Kastner DL: Horror autoinflammaticus: The molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 27:621–668. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kastner DL, Aksentijevich I and Goldbach-Mansky R: Autoinflammatory disease reloaded: A clinical perspective. Cell. 140:784–790. 2010. View Article : Google Scholar : PubMed/NCBI
12	Gerfaud-Valentin M, Jamilloux Y, Iwaz J and Sève P: Adult-onset Still's disease. Autoimmun Rev. 13:708–722. 2014. View Article : Google Scholar : PubMed/NCBI
13	Kadavath S and Efthimiou P: Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options. Ann Med. 47:6–14. 2015. View Article : Google Scholar : PubMed/NCBI
14	Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T, et al: Preliminary criteria for classification of adult Still's disease. J Rheumatol. 19:424–430. 1992.PubMed/NCBI
15	Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Miyawaki S, Amano T, Takeuchi T and Makino H: Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease. Arthritis Rheum. 44:550–560. 2001. View Article : Google Scholar : PubMed/NCBI
16	Choi JH, Suh CH, Lee YM, Suh YJ, Lee SK, Kim SS, Nahm DH and Park HS: Serum cytokine profiles in patients with adult onset Still's disease. J Rheumatol. 30:2422–2427. 2003.PubMed/NCBI
17	Chen DY, Chen YM, Lan JL, Lin CC, Chen HH and Hsieh CW: Potential role of Th17 cells in the pathogenesis of adult-onset still's disease. Rheumatology (Oxford). 49:2305–2312. 2010. View Article : Google Scholar : PubMed/NCBI
18	Priori R, Barone F, Alessandri C, Colafrancesco S, McInnes IB, Pitzalis C, Valesini G and Bombardieri M: Markely increased IL-18 liver expression in adult-onset Still's disease-related hepatitis. Rheumatology (Oxford). 50:776–780. 2011. View Article : Google Scholar : PubMed/NCBI
19	Young NS and Brown KE: Parvovirus B19. N Engl J Med. 350:586–597. 2004. View Article : Google Scholar : PubMed/NCBI
20	Dorsch S, Liebisch G, Kaufmann B, von Landenberg P, Hoffmann JH, Drobnik W and Modrow S: The VP1 unique region of parvovirus B19 and its constituent phospholipase A2-like activity. J Virol. 76:2014–2018. 2002. View Article : Google Scholar : PubMed/NCBI
21	Adamson-Small LA, Ignatovich IV, Laemmerhirt MG and Hobbs JA: Persistent parvovirus B19 infection in non-erythroid tissues: Possible role in the inflammatory and disease process. Virus Res. 190:8–16. 2014. View Article : Google Scholar : PubMed/NCBI
22	Chen DY, Chen YM, Lan JL, Tzang BS, Lin CC and Hsu TC: Significant association of past parvovirus B19 infection with cytopenia in both adult-onset Still's disease and systemic lupus erythematosus patients. Clin Chim Acta. 413:855–860. 2012. View Article : Google Scholar : PubMed/NCBI
23	Chomczynski P and Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 162:156–159. 1987. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Tzang BS, Tsay GJ, Lee YJ, Li C, Sun YS and Hsu TC: The association of VP1 unique region protein in acute parvovirus B19 infection and anti-phospholipid antibody production. Clin Chim Acta. 378:59–65. 2007. View Article : Google Scholar : PubMed/NCBI
26	Pontillo A, Girardelli M, Kamada AJ, Pancotto JA, Donadi EA, Crovella S and Sandrin-Garcia P: Polymorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity. 45:271–278. 2012. View Article : Google Scholar : PubMed/NCBI
27	Tschopp J and Schroder K: NLRP3 inflammasome activation: The convergence of multiple signaling pathways on ROS production. Nat Rev Immunol. 10:210–215. 2010. View Article : Google Scholar : PubMed/NCBI
28	Bostanci N, Emingil G, Saygan B, Turkoglu O, Atilla G, Curtis MA and Belibasakis GN: Expression and regulation of the NALP3 inflammasome complex in periodontal diseases. Clin Exp Immunol. 157:415–422. 2009. View Article : Google Scholar : PubMed/NCBI
29	Bruey JM, Bruey-Sedano N, Newman R, Chandler S, Stehlik C and Reed JC: PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. J Biol Chem. 279:51897–51907. 2004. View Article : Google Scholar : PubMed/NCBI
30	Radian AD, de Almeida L, Dorfleutner A and Stehlik C: NLRP7 and related inflammasome activating pattern recognition receptors and their function in host defense and disease. Microbes Infect. 15:630–639. 2013. View Article : Google Scholar : PubMed/NCBI
31	Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y and Stehlik C: An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity. 36:464–476. 2012. View Article : Google Scholar : PubMed/NCBI
32	Kinoshita T, Wang Y, Hasegawa M, Imamura R and Suda T: PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion. J Biol Chem. 280:21720–21725. 2005. View Article : Google Scholar : PubMed/NCBI
33	Pinheiro AS, Eibl C, Ekman-Vural Z, Schwarzenbacher R and Peti W: The NLRP12 pyrin domain: Structure, dynamics, and functional insights. J Mol Biol. 413:790–803. 2011. View Article : Google Scholar : PubMed/NCBI
34	Tadaki H, Saitsu H, Nishimura-Tadaki A, Imagawa T, Kikuchi M, Hara R, Kaneko U, Kishi T, Miyamae T, Miyake N, et al: De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis. J Hum Genet. 56:343–347. 2011. View Article : Google Scholar : PubMed/NCBI
35	Wang Y, Hasegawa M, Imamura R, Kinoshita T, Kondo C, Konaka K and Suda T: PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Int Immunol. 16:777–786. 2004. View Article : Google Scholar : PubMed/NCBI
36	Fernandes R, Tsuda C, Perumalsamy AL, Naranian T, Chong J, Acton BM, Tong ZB, Nelson LM and Jurisicova A: NLRP5 mediates mitochondrial function in mouse oocytes and embryos. Biol Reprod. 86:138, 1–10. 2012. View Article : Google Scholar
37	Barlan AU, Griffin TM, McGuire KA and Wiethoff CM: Adenovirus membrane penetration activates the NLRP3 inflammasome. J Virol. 85:146–155. 2011. View Article : Google Scholar : PubMed/NCBI