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Published in: BMC Medicine 1/2024

Open Access 01-12-2024 | Liver Cirrhosis | Research article

Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure

Authors: Hozeifa Mohamed Hassan, Xi Liang, Jiaojiao Xin, Yingyan Lu, Qun Cai, Dongyan Shi, Keke Ren, Jun Li, Qi Chen, Jiang Li, Peng Li, Beibei Guo, Hui Yang, Jinjin Luo, Heng Yao, Xingping Zhou, Wen Hu, Jing Jiang, Jun Li

Published in: BMC Medicine | Issue 1/2024

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Abstract

Background

The key role of thrombospondin 1 (THBS1) in the pathogenesis of acute-on-chronic liver failure (ACLF) is unclear. Here, we present a transcriptome approach to evaluate THBS1 as a potential biomarker in ACLF disease pathogenesis.

Methods

Biobanked peripheral blood mononuclear cells (PBMCs) from 330 subjects with hepatitis B virus (HBV)-related etiologies, including HBV-ACLF, liver cirrhosis (LC), and chronic hepatitis B (CHB), and normal controls (NC) randomly selected from the Chinese Group on the Study of Severe Hepatitis B (COSSH) prospective multicenter cohort underwent transcriptome analyses (ACLF = 20; LC = 10; CHB = 10; NC = 15); the findings were externally validated in participants from COSSH cohort, an ACLF rat model and hepatocyte-specific THBS1 knockout mice.

Results

THBS1 was the top significantly differentially expressed gene in the PBMC transcriptome, with the most significant upregulation in ACLF, and quantitative polymerase chain reaction (ACLF = 110; LC = 60; CHB = 60; NC = 45) was used to verify that THBS1 expression corresponded to ACLF disease severity outcome, including inflammation and hepatocellular apoptosis. THBS1 showed good predictive ability for ACLF short-term mortality, with an area under the receiver operating characteristic curve (AUROC) of 0.8438 and 0.7778 at 28 and 90 days, respectively. Enzyme-linked immunosorbent assay validation of the plasma THBS1 using an expanded COSSH cohort subjects (ACLF = 198; LC = 50; CHB = 50; NC = 50) showed significant correlation between THBS1 with ALT and γ-GT (P = 0.01), and offered a similarly good prognostication predictive ability (AUROC = 0.7445 and 0.7175) at 28 and 90 days, respectively. ACLF patients with high-risk short-term mortality were identified based on plasma THBS1 optimal cut-off value (< 28 µg/ml). External validation in ACLF rat serum and livers confirmed the functional association between THBS1, the immune response and hepatocellular apoptosis. Hepatocyte-specific THBS1 knockout improved mouse survival, significantly repressed major inflammatory cytokines, enhanced the expression of several anti-inflammatory mediators and impeded hepatocellular apoptosis.

Conclusions

THBS1 might be an ACLF disease development-related biomarker, promoting inflammatory responses and hepatocellular apoptosis, that could provide clinicians with a new molecular target for improving diagnostic and therapeutic strategies.

Graphical Abstract

Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Moreau R, Claria J, Aguilar F, Fenaille F, Lozano JJ, Junot C, et al. Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF. J Hepatol. 2020;72(4):688–701.PubMedCrossRef
5.
Arroyo V, Angeli P, Moreau R, Jalan R, Clària J, Trebicka J, et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol. 2021;74(3):670–85.PubMedCrossRef
6.
Zaccherini G, Aguilar F, Caraceni P, Claria J, Lozano JJ, Fenaille F, et al. Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF. J Hepatol. 2021;74(5):1117–31.PubMedCrossRef
7.
Li J, Liang X, Jiang J, Yang L, Xin J, Shi D, et al. PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF. Gut. 2022;71(1):163–75.PubMedCrossRef
8.
Granito A, Muratori P, Muratori L. Acute-on-chronic liver failure: a complex clinical entity in patients with autoimmune hepatitis. J Hepatol. 2021;75(6):1503–5.PubMedCrossRef
9.
Devarbhavi H, Choudhury AK, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, et al. Drug-induced acute-on-chronic liver failure in Asian patients. Am J Gastroenterol. 2019;114(6):929–37.PubMedCrossRef
10.
Liu Z, Morgan S, Ren J, Wang Q, Annis DS, Mosher DF, et al. Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm. Circ Res. 2015;117(2):129–41.PubMedPubMedCentralCrossRef
11.
Jefferson B, Ali M, Grant S, Frampton G, Ploof M, Andry S, et al. Thrombospondin-1 exacerbates acute liver failure and hepatic encephalopathy pathology in mice by activating transforming growth factor β1. Am J Pathol. 2020;190(2):347–57.PubMedPubMedCentralCrossRef
12.
Grimbert P, Bouguermouh S, Baba N, Nakajima T, Allakhverdi Z, Braun D, et al. Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation. J Immunol. 2006;177(6):3534–41.PubMedCrossRef
13.
Li Y, Turpin CP, Wang S. Role of thrombospondin 1 in liver diseases. Hepatol Res. 2017;47(2):186–93.PubMedCrossRef
14.
Zhou Q, Ding W, Jiang L, Xin J, Wu T, Shi D, et al. Comparative transcriptome analysis of peripheral blood mononuclear cells in hepatitis B-related acute-on-chronic liver failure. Sci Rep. 2016;6:20759.ADSPubMedPubMedCentralCrossRef
15.
Wu T, Li J, Shao L, Xin J, Jiang L, Zhou Q, et al. Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure. Gut. 2018;67(12):2181–91.PubMedCrossRef
16.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–83.PubMedCrossRef
17.
Li J, Liang X, You S, Feng T, Zhou X, Zhu B, et al. Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure. J Hepatol. 2021;75(5):1104–15.PubMedCrossRef
18.
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics (Oxford, England). 2014;30(15):2114–20.PubMed
19.
20.
Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33(3):290–5.PubMedPubMedCentralCrossRef
21.
Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016;11(9):1650–67.PubMedPubMedCentralCrossRef
22.
Hassan HM, Cai Q, Liang X, Xin J, Ren K, Jiang J, et al. Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats. Life Sci Alliance. 2022;5(3):e202101189.PubMedCrossRef
23.
Zheng Z, Wu L, Han Y, Chen J, Zhu S, Yao Y, et al. Gut microbiota-controlled tryptophan metabolism improves D-Gal/LPS-induced acute liver failure in C57BL/6 mice. Engineering. 2022;14:134–46.CrossRef
24.
Gehrke N, Hövelmeyer N, Waisman A, Straub BK, Weinmann-Menke J, Wörns MA, et al. Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation. J Hepatol. 2018;68(5):986–95.PubMedCrossRef
25.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods (San Diego, Calif). 2001;25(4):402–8.PubMedCrossRef
26.
Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.PubMedCrossRef
27.
Parra ER, Jiang M, Solis L, Mino B, Laberiano C, Hernandez S, et al. Procedural requirements and recommendations for multiplex immunofluorescence tyramide signal amplification assays to support translational oncology studies. Cancers (Basel). 2020;12(2):255.PubMedCrossRef
28.
Sun S, Guo Y, Zhao G, Zhou X, Li J, Hu J, et al. Complement and the alternative pathway play an important role in LPS/D-GalN-induced fulminant hepatic failure. PLoS One. 2011;6(11):e26838.ADSPubMedPubMedCentralCrossRef
29.
Li L, Duan C, Zhao Y, Zhang X, Yin H, Wang T, et al. Preventive effects of interleukin-6 in lipopolysaccharide/d-galactosamine induced acute liver injury via regulating inflammatory response in hepatic macrophages. Int Immunopharmacol. 2017;51:99–106.PubMedCrossRef
30.
Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. J Hepatol. 2012;57(6):1336–48.PubMedCrossRef
31.
Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A. Acute-on-chronic liver failure. Lancet. 2015;386(10003):1576–87.PubMedCrossRef
32.
Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426–37, 37.e1-9.PubMedCrossRef
33.
Bajaj JS, O’Leary JG, Reddy KR, Wong F, Biggins SW, Patton H, et al. Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology (Baltimore, MD). 2014;60(1):250–6.PubMedCrossRef
34.
Shi Y, Yang Y, Hu Y, Wu W, Yang Q, Zheng M, et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology. 2015;62(1):232–42.PubMedCrossRef
35.
Wu D, Zhang S, Xie Z, Chen E, Rao Q, Liu X, et al. Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure. J Clin Investig. 2020;130(4):2069–80.PubMedPubMedCentralCrossRef
36.
Nielsen MC, HvidbjergGantzel R, Clària J, Trebicka J, Møller HJ, Grønbæk H. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure. Cells. 2020;9(5):1175.PubMedPubMedCentralCrossRef
37.
Grønbæk H, Rødgaard-Hansen S, Aagaard NK, Arroyo V, Moestrup SK, Garcia E, et al. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). J Hepatol. 2016;64(4):813–22.PubMedCrossRef
38.
39.
Luo J, Liang X, Xin J, Li J, Li P, Zhou Q, et al. Predicting the onset of hepatitis B virus-related acute-on-chronic liver failure. Clin Gastroenterol Hepatol. 2023;21(3):681–93.PubMedCrossRef
40.
Luo J, Liang X, Xin J, Li P, Li J, Jiang J, et al. Serum ferritin diagnosis and prediction of hepatitis B virus-related acute-on-chronic liver failure. J Med Virol. 2023;95(1):e28183.PubMedCrossRef
41.
MacParland SA, Liu JC, Ma XZ, Innes BT, Bartczak AM, Gage BK, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018;9(1):4383.ADSPubMedPubMedCentralCrossRef
42.
Wu ZB, Zheng YB, Wang K, Mo ZS, Zhen X, Yan Y, et al. Plasma interleukin-6 level: a potential prognostic indicator of emergent HBV-associated ACLF. Can J Gastroenterol Hepatol. 2021;2021:5545181.PubMedPubMedCentralCrossRef
43.
Qin G, Wang B, Zhang G, Wu L, Zhu P, Zhang Q. Bikunin: a promising prognostic biomarker for acute-on-chronic liver failure in patients with viral hepatitis B. Infect Drug Resist. 2023;16:5765–75.PubMedPubMedCentralCrossRef
44.
Cai J, Han T, Nie C, Jia X, Liu Y, Zhu Z, et al. Biomarkers of oxidation stress, inflammation, necrosis and apoptosis are associated with hepatitis B-related acute-on-chronic liver failure. Clin Res Hepatol Gastroenterol. 2016;40(1):41–50.PubMedCrossRef
45.
Du XX, Shi Y, Yang Y, Yu Y, Lou HG, Lv FF, et al. DAMP molecular IL-33 augments monocytic inflammatory storm in hepatitis B-precipitated acute-on-chronic liver failure. Liver Int. 2018;38(2):229–38.PubMedCrossRef
46.
Monteiro S, Grandt J, Uschner FE, Kimer N, Madsen JL, Schierwagen R, et al. Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation. Gut. 2021;70(2):379–87.PubMed
47.
Yao J, Liu T, Zhao Q, Ji Y, Bai J, Wang H, et al. Genetic landscape and immune mechanism of monocytes associated with the progression of acute-on-chronic liver failure. Hepatol Int. 2023;17(3):676–88.PubMedCrossRef
48.
Matsuo Y, Tanaka M, Yamakage H, Sasaki Y, Muranaka K, Hata H, et al. Thrombospondin 1 as a novel biological marker of obesity and metabolic syndrome. Metab Clin Exp. 2015;64(11):1490–9.PubMedCrossRef
49.
McMorrow JP, Crean D, Gogarty M, Smyth A, Connolly M, Cummins E, et al. Tumor necrosis factor inhibition modulates thrombospondin-1 expression in human inflammatory joint disease through altered NR4A2 activity. Am J Pathol. 2013;183(4):1243–57.PubMedCrossRef
50.
Contreras-Ruiz L, Ryan DS, Sia RK, Bower KS, Dartt DA, Masli S. Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology. 2014;121(7):1389–97.PubMedCrossRef
51.
Ortiz-Masia D, Diez I, Calatayud S, Hernandez C, Cosin-Roger J, Hinojosa J, et al. Induction of CD36 and thrombospondin-1 in macrophages by hypoxia-inducible factor 1 and its relevance in the inflammatory process. PLoS One. 2012;7(10):e48535.ADSPubMedPubMedCentralCrossRef
52.
Frampton G, Reddy P, Jefferson B, Ali M, Khan D, McMillin M. Inhibition of thrombospondin-1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice. Toxicol Appl Pharmacol. 2020;409:115323.PubMedPubMedCentralCrossRef
53.
Starlinger P, Haegele S, Wanek D, Zikeli S, Schauer D, Alidzanovic L, et al. Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction. Br J Surg. 2015;102(7):826–36.PubMedCrossRef
54.
Liu X, Hamnvik OP, Chamberland JP, Petrou M, Gong H, Christophi CA, et al. Circulating alanine transaminase (ALT) and γ-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study. Metab Clin Exp. 2014;63(6):773–82.PubMedCrossRef
55.
56.
Gutierrez LS, Gutierrez J. Thrombospondin 1 in metabolic diseases. Front Endocrinol. 2021;12:638536.CrossRef
57.
58.
Breitkopf K, Sawitza I, Westhoff JH, Wickert L, Dooley S, Gressner AM. Thrombospondin 1 acts as a strong promoter of transforming growth factor beta effects via two distinct mechanisms in hepatic stellate cells. Gut. 2005;54(5):673–81.PubMedPubMedCentralCrossRef
59.
Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Sargent MA, Blair NS, et al. A thrombospondin-dependent pathway for a protective ER stress response. Cell. 2012;149(6):1257–68.PubMedPubMedCentralCrossRef
60.
Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, et al. Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med. 2003;198(8):1277–83.PubMedPubMedCentralCrossRef
61.
62.
Bige N, Shweke N, Benhassine S, Jouanneau C, Vandermeersch S, Dussaule JC, et al. Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction. Kidney Int. 2012;81(12):1226–38.PubMedCrossRef
63.
Min-DeBartolo J, Schlerman F, Akare S, Wang J, McMahon J, Zhan Y, et al. Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH). PLoS One. 2019;14(12):e0226854.PubMedPubMedCentralCrossRef
64.
Desai P, Helkin A, Odugbesi A, Stein J, Bruch D, Lawler J, et al. Fluvastatin inhibits intimal hyperplasia in wild-type but not Thbs1-null mice. J Surg Res. 2017;210:1–7.PubMedCrossRef
65.
Hayashi H, Sakai K, Baba H, Sakai T. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice. Hepatology. 2012;55(5):1562–73.PubMedCrossRef
66.
Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6(1):41–8.PubMedCrossRef
67.
68.
Mirochnik Y, Kwiatek A, Volpert OV. Thrombospondin and apoptosis: molecular mechanisms and use for design of complementation treatments. Curr Drug Targets. 2008;9(10):851–62.PubMedPubMedCentralCrossRef
69.
Li H, Xia Q, Zeng B, Li ST, Liu H, Li Q, et al. Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation. J Hepatol. 2015;63(1):50–9.PubMedCrossRef
70.
Trovato FM, Zia R, Artru F, Mujib S, Jerome E, Cavazza A, et al. Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure. J Hepatol. 2023;78(3):558–73.PubMedCrossRef
71.
Imaoka K, Doi K, Doi C, Toriumi W, Honjo K, Mitsuoka T. Mouse strain difference in bile duct lesions induced by swine serum injections. Lab Anim. 1986;20(4):321–4.PubMedCrossRef
Metadata
Title
Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure
Authors
Hozeifa Mohamed Hassan
Xi Liang
Jiaojiao Xin
Yingyan Lu
Qun Cai
Dongyan Shi
Keke Ren
Jun Li
Qi Chen
Jiang Li
Peng Li
Beibei Guo
Hui Yang
Jinjin Luo
Heng Yao
Xingping Zhou
Wen Hu
Jing Jiang
Jun Li
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2024
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-024-03318-x

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