{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:14:16Z","timestamp":1780578856894,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T00:00:00Z","timestamp":1656892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the University of Pisa"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R\/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD\/NASH associated with chronic HCV infection than those with metabolic damage only (p \u2264 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.<\/jats:p>","DOI":"10.3390\/ijms23137447","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T11:15:05Z","timestamp":1656933305000},"page":"7447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity\/Severity of Viral or Metabolic Liver Damage"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5724-268X","authenticated-orcid":false,"given":"Chiara","family":"Rossi","sequence":"first","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9779-2731","authenticated-orcid":false,"given":"Antonio","family":"Salvati","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliero-Universitaria Pisana, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-7877","authenticated-orcid":false,"given":"Mariarosaria","family":"Distaso","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Campani","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Raggi","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Biancalana","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Tric\u00f2","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-9152","authenticated-orcid":false,"given":"Maurizia Rossana","family":"Brunetto","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7855-8253","authenticated-orcid":false,"given":"Anna","family":"Solini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Via Roma 67, I-56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e10248","DOI":"10.15252\/emmm.201810248","article-title":"Inflammasomes in neuroinflammatory and neurodegenerative diseases","volume":"11","author":"Voet","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.bcp.2017.12.021","article-title":"The P2X7 receptor: A main player in inflammation","volume":"151","author":"Adinolfi","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fphys.2013.00216","article-title":"The relationship between P2X4 and P2X7: A physiologically important interaction?","volume":"4","author":"Craigie","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fusco, R., Siracusa, R., Genovese, T., Cuzzocrea, S., and Di Paola, R. (2020). Focus on the Role of NLRP3 Inflammasome in Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124223"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1002\/eji.201848070","article-title":"Role of AIM2 inflammasome in inflammatory diseases, cancer and infection","volume":"49","author":"Sharma","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/nature07725","article-title":"AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC","volume":"458","author":"Hornung","year":"2009","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrgastro.2015.94","article-title":"Inflammasome activation and function in liver disease","volume":"12","author":"Szabo","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.cyto.2018.04.032","article-title":"The role of the NLRP3 inflammasome and the activation of IL-1\u03b2 in the pathogenesis of chronic viral hepatic inflammation","volume":"110","author":"Molyvdas","year":"2018","journal-title":"Cytokine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1089\/vim.2016.0008","article-title":"Ionotropic Purinergic Receptors P2X4 and P2X7:Proviral or Antiviral? An Insight into P2X Receptor Signaling and Hepatitis C Virus Infection","volume":"29","author":"Manzoor","year":"2016","journal-title":"Viral Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"G950","DOI":"10.1152\/ajpgi.00235.2013","article-title":"Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis","volume":"305","author":"Das","year":"2013","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8962458","DOI":"10.1155\/2017\/8962458","article-title":"Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome","volume":"2017","author":"Menini","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.humimm.2013.01.022","article-title":"Correlation of AIM2 expression in peripheral blood mononuclear cells from humans with acute and chronic hepatitis B","volume":"74","author":"Wu","year":"2013","journal-title":"Hum. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1089\/vim.2018.0058","article-title":"Differential Activation of NLRP3, AIM2, and IFI16 Inflammasomes in Humans with Acute and Chronic Hepatitis B","volume":"31","author":"Chen","year":"2018","journal-title":"Viral Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12985-015-0360-y","article-title":"Expression of AIM2 is correlated with increased inflammation in chronic hepatitis B patients","volume":"12","author":"Han","year":"2015","journal-title":"Virol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6489012","DOI":"10.1155\/2016\/6489012","article-title":"Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH","volume":"2016","author":"Wan","year":"2016","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrgastro.2017.35","article-title":"A critical role for the NLRP3 inflammasome in NASH","volume":"14","author":"Thomas","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1089\/vim.2015.0093","article-title":"Evaluating the Role of Cellular Immune Responses in the Emergence of HCV NS3 Resistance Mutations During Protease Inhibitor Therapy","volume":"29","author":"Rouster","year":"2016","journal-title":"Viral Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, J., Tian, Y., Chan, S.T., Kim, J.Y., Cho, C., and Ou, J.H. (2015). TNF-\u03b1 Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004937"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Baeza-Raja, B., Goodyear, A., Liu, X., Lam, K., Yamamoto, L., Li, Y., Dodson, G.S., Takeuchi, T., Kisseleva, T., and Brenner, D.A. (2020). Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234038"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1089\/vim.2013.0044","article-title":"Transcript analysis of P2X receptors in PBMCs of chronic HCV patients: An insight into antiviral treatment response and HCV-induced pathogenesis","volume":"26","author":"Ashraf","year":"2013","journal-title":"Viral Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1007\/s11033-018-4432-0","article-title":"Purinoceptor expression in hepatocellular virus (HCV)-induced and non-HCV hepatocellular carcinoma: An insight into the proviral role of the P2X4 receptor","volume":"45","author":"Khalid","year":"2018","journal-title":"Mol. Biol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fimmu.2020.00113","article-title":"Evolutionary Origin of the P2X7 C-ter Region: Capture of an Ancient Ballast Domain by a P2X4-Like Gene in Ancient Jawed Vertebrates","volume":"11","author":"Rump","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1748-1716.2010.02225.x","article-title":"Purinergic signalling in epithelial ion transport: Regulation of secretion and absorption","volume":"202","author":"Novak","year":"2011","journal-title":"Acta Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.coph.2019.03.010","article-title":"Targeting P2X4 and P2X7 receptors in multiple sclerosis","volume":"47","author":"Domercq","year":"2019","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s11302-019-09675-0","article-title":"Role of purinergic receptors in hepatobiliary carcinoma in Pakistani population: An approach towards proinflammatory role of P2X4 and P2X7 receptors","volume":"15","author":"Asif","year":"2019","journal-title":"Purinergic Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16222","DOI":"10.1038\/srep16222","article-title":"Modulation of P2X4\/P2X7\/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death","volume":"5","author":"Draganov","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1186\/1743-422X-8-431","article-title":"Identification of ionotrophic purinergic receptors in Huh-7 cells and their response towards structural proteins of HCV genotype 3a","volume":"8","author":"Manzoor","year":"2011","journal-title":"Virol. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/imr.12279","article-title":"Hepatitis regulation by the inflammasome signaling pathway","volume":"265","author":"Negash","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.4049\/jimmunol.1600714","article-title":"AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality","volume":"198","author":"Zhang","year":"2017","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s11262-016-1327-9","article-title":"Human hepatocytes express absent in melanoma 2 and respond to hepatitis B virus with interleukin-18 expression","volume":"52","author":"Pan","year":"2016","journal-title":"Virus Genes."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"G1034","DOI":"10.1152\/ajpgi.00431.2020","article-title":"Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in non-alcoholic fatty liver disease","volume":"320","author":"Xu","year":"2021","journal-title":"Am. J. Physiol. Gastrointest Liver Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1111\/liv.12537","article-title":"Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis","volume":"34","author":"Csak","year":"2014","journal-title":"Liver Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.0309-0167.2004.01798.x","article-title":"Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors","volume":"44","author":"Slater","year":"2004","journal-title":"Histopathology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49664","DOI":"10.18632\/oncotarget.10430","article-title":"P2X7 targeting inhibits growth of human mesothelioma","volume":"7","author":"Amoroso","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/hep.510240402","article-title":"Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines","volume":"24","author":"Napoli","year":"1996","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Seidler, S., Zimmermann, H.W., Weiskirchen, R., Trautwein, C., and Tacke, F. (2012). Elevated circulating soluble interleukin-2 receptor in patients with chronic liver diseases is associated with non-classical monocytes. BMC Gastroenterol., 12.","DOI":"10.1186\/1471-230X-12-38"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/hep.28776","article-title":"Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease","volume":"65","author":"Ajmera","year":"2017","journal-title":"Hepatology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1111\/j.1365-2893.2006.00811.x","article-title":"Transient elastography: A new surrogate marker of liver fibrosis influenced by major changes of transaminases","volume":"14","author":"Coco","year":"2007","journal-title":"J. Viral Hepat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1111\/j.1572-0241.1999.01377.x","article-title":"Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions","volume":"94","author":"Brunt","year":"1999","journal-title":"Am. J. Gastroenterol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:42:42Z","timestamp":1760139762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,4]]},"references-count":41,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137447"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137447","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,4]]}}}