Detection of inflammasome activation in liver tissue during the donation process as potential biomarker for liver transplantation.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
30 May 2024
30 May 2024
Historique:
received:
18
04
2024
accepted:
22
05
2024
revised:
17
05
2024
medline:
31
5
2024
pubmed:
31
5
2024
entrez:
30
5
2024
Statut:
epublish
Résumé
Deceased donor liver transplantation (LT) is a crucial lifesaving option for patients with end-stage liver diseases. Although donation after brain death (DBD) remains the main source of donated organs, exploration of donation after circulatory death (DCD) addresses donor scarcity but introduces challenges due to warm ischemia. While technical advances have improved outcomes, challenges persist, with a 13% mortality rate within the first year. Delving into liver transplantation complexities reveals the profound impact of molecular signaling on organ fate. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation play a pivotal role, influencing inflammatory responses. The NLRP3 inflammasome, found in hepatocytes, contributes to inflammation, fibrosis, and liver cell death. This study explores these dynamics, shedding light on potential biomarkers and therapeutic targets. Samples from 36 liver transplant patients were analyzed for ASC specks detection and inflammasome-related gene expression. Liver biopsies, obtained before and after cold ischemia storage, were processed for immunofluorescence, qRT-PCR, and Western blot. One year post-LT clinical follow-up included diagnostic procedures for complications, and global survival was assessed. Immunofluorescence detected activated inflammasome complexes in fixed liver tissues. ASC specks were identified in hepatocytes, showing a trend toward more specks in DCD livers. Likewise, inflammasome-related gene expression analysis indicated higher expression in DCD livers, decreasing after cold ischemia. Similar results were found at protein level. Patients with increased ASC specks staining exhibited lower overall survival rates, correlating with IL1B expression after cold ischemia. Although preliminary, these findings offer novel insights into utilizing direct detection of inflammasome activation in liver tissue as a biomarker. They suggest its potential impact on post-transplant outcomes, potentially paving the way for improved diagnostic approaches and personalized treatment strategies in LT.
Identifiants
pubmed: 38816358
doi: 10.1038/s41420-024-02042-y
pii: 10.1038/s41420-024-02042-y
doi:
Types de publication
Journal Article
Langues
eng
Pagination
266Subventions
Organisme : Fundación Mutua Madrileña (Mutua Madrileña Foundation)
ID : AP171362019
Organisme : Fundación Séneca (Fundacion Seneca)
ID : 22257PDC23
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI20/00185
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : DTS23/00013
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : FI21/00073
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI23/00321
Informations de copyright
© 2024. The Author(s).
Références
Seehofer D, Schoning W, Neuhaus P. Deceased donor liver transplantation. Chirurg. 2013;84:391–7.
pubmed: 23576123
doi: 10.1007/s00104-012-2413-8
Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J. Hepatol. 2019;70:151–71.
pubmed: 30266282
doi: 10.1016/j.jhep.2018.09.014
Saidi RF, Hejazii Kenari SK. Challenges of organ shortage for transplantation: solutions and opportunities. Int J Organ Transpl. Med. 2014;5:87–96.
Potter KF, Cocchiola B, Quader MA. Donation after circulatory death: opportunities on the horizon. Curr Opin Anaesthesiol. 2021;34:168–72.
pubmed: 33560667
doi: 10.1097/ACO.0000000000000960
Croome KP, Taner CB. The Changing Landscapes in DCD Liver Transplantation. Curr. Transpl. Rep. 2020;7:194–204.
pubmed: 32837828
doi: 10.1007/s40472-020-00283-1
Forde JJ, Bhamidimarri KR. Management of Biliary Complications in Liver Transplant Recipients. Clin. Liver Dis. 2022;26:81–99.
pubmed: 34802665
doi: 10.1016/j.cld.2021.08.008
Rodriguez-Peralvarez M, Rico-Juri JM, Tsochatzis E, Burra P, De la Mata M, Lerut J. Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal. Transpl. Int. 2016;29:961–73.
pubmed: 26714264
doi: 10.1111/tri.12737
Luo X, Nicoarä-Farcäu O, Magaz M, Betancourt F, Soy g, Baiges A, et al. Obstruction of the liver circulation. In: Taniguchi T, Lee S, editors. Cardio-Hepatology Connections Between Hepatic and Cardiovascular Disease: Academic Press; 2023. p. 65–92.
Lucas-Ruiz F, Mateo SV, Jover-Aguilar M, Alconchel F, Martinez-Alarcon L, de Torre-Minguela C, et al. Danger signals released during cold ischemia storage activate NLRP3 inflammasome in myeloid cells and influence early allograft function in liver transplantation. EBioMedicine. 2023;87:104419.
pubmed: 36543018
doi: 10.1016/j.ebiom.2022.104419
Villalba-Lopez F, Garcia-Bernal D, Mateo SV, Vidal-Correoso D, Jover-Aguilar M, Alconchel F, et al. Endothelial cell activation mediated by cold ischemia-released mitochondria is partially inhibited by defibrotide and impacts on early allograft function following liver transplantation. Biomed. Pharmacother. 2023;167:115529.
pubmed: 37729732
doi: 10.1016/j.biopha.2023.115529
Barnett KC, Li S, Liang K, Ting JP. A 360 degrees view of the inflammasome: Mechanisms of activation, cell death, and diseases. Cell. 2023;186:2288–312.
pubmed: 37236155
pmcid: 10228754
doi: 10.1016/j.cell.2023.04.025
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell. 2002;10:417–26.
pubmed: 12191486
doi: 10.1016/S1097-2765(02)00599-3
de Torre-Minguela C, Mesa Del Castillo P, Pelegrin P. The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases. Front Immunol. 2017;8:43.
pubmed: 28191008
pmcid: 5271383
Lucas-Ruiz F, Penin-Franch A, Pons JA, Ramirez P, Pelegrin P, Cuevas S, et al. Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation. Int J Mol Sci. 2022;23:14396.
Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59:898–910.
pubmed: 23813842
doi: 10.1002/hep.26592
Gaul S, Leszczynska A, Alegre F, Kaufmann B, Johnson CD, Adams LA, et al. Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis. J Hepatol. 2021;74:156–67.
pubmed: 32763266
doi: 10.1016/j.jhep.2020.07.041
Stutz A, Horvath GL, Monks BG, Latz E. ASC speck formation as a readout for inflammasome activation. Methods Mol Biol. 2013;1040:91–101.
pubmed: 23852599
doi: 10.1007/978-1-62703-523-1_8
Soriano-Teruel PM, Garcia-Lainez G, Marco-Salvador M, Pardo J, Arias M, DeFord C, et al. Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases. Cell Death Dis. 2021;12:1155.
pubmed: 34903717
pmcid: 8667020
doi: 10.1038/s41419-021-04420-1
Pareja E, Cortes M, Hervas D, Mir J, Valdivieso A, Castell JV, et al. A score model for the continuous grading of early allograft dysfunction severity. Liver Transpl. 2015;21:38–46.
pubmed: 25204890
doi: 10.1002/lt.23990
Matesanz R, Dominguez-Gil B, Coll E, Mahillo B, Marazuela R. How Spain Reached 40 Deceased Organ Donors per Million Population. Am J Transpl. 2017;17:1447–54.
doi: 10.1111/ajt.14104
Siddiqui F, Al-Adwan Y, Subramanian J, Henry ML. Contemporary considerations in solid organ transplantation utilizing DCD donors. Transplant Rep. 2022;7:100118.
Danion J, Thuillier R, Allain G, Bruneval P, Tomasi J, Pinsard M, et al. Evaluation of Liver Quality after Circulatory Death Versus Brain Death: A Comparative Preclinical Pig Model Study. Int J Mol Sci. 2020;21: 9040.
Fu J, Wu H. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu Rev. Immunol. 2023;41:301–16.
pubmed: 36750315
pmcid: 10159982
doi: 10.1146/annurev-immunol-081022-021207
Xiao L, Magupalli VG, Wu H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature. 2023;613:595–600.
pubmed: 36442502
doi: 10.1038/s41586-022-05570-8
Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA. 2011;108:19725–30.
pubmed: 22106299
pmcid: 3241791
doi: 10.1073/pnas.1108586108
Faner R, Sobradillo P, Noguera A, Gomez C, Cruz T, Lopez-Giraldo A, et al. The inflammasome pathway in stable COPD and acute exacerbations. ERJ Open Res. 2016;2:00002–2016.
Hong BJ, Liu H, Wang ZH, Zhu YX, Su LY, Zhang MX, et al. Inflammasome activation involved in early inflammation reaction after liver transplantation. Immunol Lett. 2017;190:265–71.
pubmed: 28855128
doi: 10.1016/j.imlet.2017.08.020
Yu Y, Cheng Y, Pan Q, Zhang YJ, Jia DG, Liu YF. Effect of the Selective NLRP3 Inflammasome Inhibitor mcc950 on Transplantation Outcome in a Pig Liver Transplantation Model With Organs From Donors After Circulatory Death Preserved by Hypothermic Machine Perfusion. Transplantation. 2019;103:353–62.
pubmed: 30247318
doi: 10.1097/TP.0000000000002461
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16:407–20.
pubmed: 27291964
doi: 10.1038/nri.2016.58
Ruan J, Xia S, Liu X, Lieberman J, Wu H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature. 2018;557:62–7.
pubmed: 29695864
pmcid: 6007975
doi: 10.1038/s41586-018-0058-6
Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–6.
pubmed: 33472215
doi: 10.1038/s41586-021-03218-7
Baroja-Mazo A, Martín-Sánchez F, Gomez AI, Martínez 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;15:738–48.
pubmed: 24952504
doi: 10.1038/ni.2919
Sun P, Zhong J, Liao H, Loughran P, Mulla J, Fu G, et al. Hepatocytes Are Resistant to Cell Death From Canonical and Non-Canonical Inflammasome-Activated Pyroptosis. Cell Mol Gastroenterol Hepatol. 2022;13:739–57.
pubmed: 34890842
doi: 10.1016/j.jcmgh.2021.11.009
Feng YS, Tan ZX, Wang MM, Xing Y, Dong F, Zhang F. Inhibition of NLRP3 Inflammasome: A Prospective Target for the Treatment of Ischemic Stroke. Front Cell Neurosci. 2020;14:155.
pubmed: 32581721
pmcid: 7283578
doi: 10.3389/fncel.2020.00155
Han PP, Han Y, Shen XY, Gao ZK, Bi X. NLRP3 inflammasome activation after ischemic stroke. Behav Brain Res. 2023;452:114578.
pubmed: 37437697
doi: 10.1016/j.bbr.2023.114578
Zheng Y, Xu L, Dong N, Li F. NLRP3 inflammasome: The rising star in cardiovascular diseases. Front Cardiovasc Med. 2022;9:927061.
pubmed: 36204568
pmcid: 9530053
doi: 10.3389/fcvm.2022.927061
Wang Y, Huang H, He W, Zhang S, Liu M, Wu S. Association between serum NLRP3 and malignant brain edema in patients with acute ischemic stroke. BMC Neurol. 2021;21:341.
pubmed: 34493232
pmcid: 8422708
doi: 10.1186/s12883-021-02369-4
Cheng X, Zhao H, Wen X, Li G, Guo S, Zhang D. NLRP3-inflammasome inhibition by MCC950 attenuates cardiac and pulmonary artery remodelling in heart failure with preserved ejection fraction. Life Sci. 2023;333:122185.
pubmed: 37858713
doi: 10.1016/j.lfs.2023.122185
Toldo S, Mezzaroma E, Buckley LF, Potere N, Di Nisio M, Biondi-Zoccai G, et al. Targeting the NLRP3 inflammasome in cardiovascular diseases. Pharm. Ther. 2022;236:108053.
doi: 10.1016/j.pharmthera.2021.108053
Pollara J, Edwards RW, Lin L, Bendersky VA, Brennan TV. Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction. JCI Insight. 2018;3:e121622.
pubmed: 30089724
pmcid: 6129133
doi: 10.1172/jci.insight.121622
Qiao J, Wu X, Luo Q, Wei G, Xu M, Wu Y, et al. NLRP3 regulates platelet integrin alphaIIbbeta3 outside-in signaling, hemostasis and arterial thrombosis. Haematologica. 2018;103:1568–76.
pubmed: 29794149
pmcid: 6119128
doi: 10.3324/haematol.2018.191700
Martin-Sanchez F, Compan V, Penin-Franch A, Tapia-Abellan A, Gomez AI, Banos-Gregori MC, et al. ASC oligomer favors caspase-1CARD domain recruitment after intracellular potassium efflux. J Cell Biol. 2023;222:e202003053.
pubmed: 37402211
pmcid: 10318405
doi: 10.1083/jcb.202003053
Tapia-Abellan A, Angosto-Bazarra D, Alarcon-Vila C, Banos MC, Hafner-Bratkovic I, Oliva B, et al. Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation. Sci Adv. 2021;7:eabf4468.
pubmed: 34524838
pmcid: 8443177
doi: 10.1126/sciadv.abf4468
Jimenez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Peralta C. Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury. Cells. 2019;8:1131.
pubmed: 31547621
pmcid: 6829519
doi: 10.3390/cells8101131
van Beekum CJ, Vilz TO, Glowka TR, von Websky MW, Kalff JC, Manekeller S. Normothermic Machine Perfusion (NMP) of the Liver - Current Status and Future Perspectives. Ann. Transpl. 2021;26:e931664.
Dengu F, Abbas SH, Ebeling G, Nasralla D. Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review. J Clin Med. 2020;9.
Matos LL, Trufelli DC, de Matos MG, da Silva Pinhal MA. Immunohistochemistry as an important tool in biomarkers detection and clinical practice. Biomark. Insights. 2010;5:9–20.
pubmed: 20212918
pmcid: 2832341
doi: 10.4137/BMI.S2185
O’Hurley G, Sjostedt E, Rahman A, Li B, Kampf C, Ponten F, et al. Garbage in, garbage out: a critical evaluation of strategies used for validation of immunohistochemical biomarkers. Mol. Oncol. 2014;8:783–98.
pubmed: 24725481
pmcid: 5528533
doi: 10.1016/j.molonc.2014.03.008
Dunstan RW, Wharton KA Jr, Quigley C, Lowe A. The use of immunohistochemistry for biomarker assessment-can it compete with other technologies? Toxicol. Pathol. 2011;39:988–1002.
pubmed: 21971934
doi: 10.1177/0192623311419163
Nistor A, Watson PH, Pettigrew N, Tabiti K, Dawson A, Myal Y. Real-time PCR complements immunohistochemistry in the determination of HER-2/neu status in breast cancer. BMC Clin. Pathol. 2006;6:2.
pubmed: 16420697
pmcid: 1382241
doi: 10.1186/1472-6890-6-2
Hessheimer AJ, Coll E, Torres F, Ruiz P, Gastaca M, Rivas JI, et al. Normothermic regional perfusion vs. super-rapid recovery in controlled donation after circulatory death liver transplantation. J. Hepatol. 2019;70:658–65.
pubmed: 30582980
doi: 10.1016/j.jhep.2018.12.013
Watson CJE, Hunt F, Messer S, Currie I, Large S, Sutherland A, et al. In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival. Am. J. Transpl. 2019;19:1745–58.
doi: 10.1111/ajt.15241
Hessheimer AJ, de la Rosa G, Gastaca M, Ruiz P, Otero A, Gomez M, et al. Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss. Am J Transplant. 2021.
Cascales-Campos PA, Ferreras D, Alconchel F, Febrero B, Royo-Villanova M, Martinez M, et al. Controlled donation after circulatory death up to 80 years for liver transplantation: Pushing the limit again. Am J Transpl. 2020;20:204–12.
doi: 10.1111/ajt.15537
Ormonde DG, de Boer WB, Kierath A, Bell R, Shilkin KB, House AK, et al. Banff schema for grading liver allograft rejection: utility in clinical practice. Liver Transpl Surg. 1999;5:261–8.
pubmed: 10388498
doi: 10.1002/lt.500050418
Barbera-Cremades M, Baroja-Mazo A, Gomez AI, Machado F, Di Virgilio F, Pelegrin P. P2X7 receptor-stimulation causes fever via PGE2 and IL-1beta release. FASEB J. 2012;26:2951–62.
pubmed: 22490780
doi: 10.1096/fj.12-205765
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.
pubmed: 22743772
doi: 10.1038/nmeth.2019
Baroja-Mazo A, Compan V, Martin-Sanchez F, Tapia-Abellan A, Couillin I, Pelegrin P. Early endosome autoantigen 1 regulates IL-1beta release upon caspase-1 activation independently of gasdermin D membrane permeabilization. Sci Rep. 2019;9:5788.
pubmed: 30962463
pmcid: 6453936
doi: 10.1038/s41598-019-42298-4
Kunselman AR. A brief overview of pilot studies and their sample size justification. Fertil Steril. 2024.