{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:39:49Z","timestamp":1787744389052,"version":"build-2784847793"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide. In 20-30% of patients, NAFLD can progress into non-alcoholic steatohepatitis (NASH), eventually leading to fibrosis, cirrhosis and hepatocellular carcinoma development. SerpinB3 (SB3), a hypoxia-inducible factor-2\u03b1 dependent cysteine protease inhibitor, is up-regulated in hepatocytes during progressive NAFLD and proposed to contribute to disease progression. In this study we investigated the pro-inflammatory role of SB3 by employing phorbol-myristate acetate-differentiated human THP-1 macrophages exposed <jats:italic>in vitro<\/jats:italic> to human recombinant SB3 (hrSB3) along with mice overexpressing SB3 in hepatocytes (TG\/SB3) or knockout for SB3 (KO\/SB3) in which NASH was induced by feeding methionine\/choline deficient (MCD) or a choline-deficient, L-amino acid defined (CDAA) diets. <jats:italic>In vivo<\/jats:italic> experiments showed that the induction of NASH in TG\/SB3 mice was characterized by an impressive increase of liver infiltrating macrophages that formed crown-like aggregates and by an up-regulation of hepatic transcript levels of pro-inflammatory cytokines. All these parameters and the extent of liver damage were significantly blunted in KO\/SB3 mice. <jats:italic>In vitro<\/jats:italic> experiments confirmed that hrSB3 stimulated macrophage production of M1-cytokines such as TNF\u03b1 and IL-1\u03b2 and reactive oxygen species along with that of TGF\u03b2 and VEGF through the activation of the NF-kB transcription factor. The opposite changes in liver macrophage activation observed in TG\/SB3 or KO\/SB3 mice with NASH were associated with a parallel modulation in the expression of triggering receptor expressed on myeloid cells-2 (TREM2), CD9 and galectin-3 markers, recently detected in NASH-associated macrophages. From these results we propose that SB3, produced by activated\/injured hepatocytes, may operate as a pro-inflammatory mediator in NASH contributing to the disease progression.<\/jats:p>","DOI":"10.3389\/fimmu.2022.910526","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T06:06:12Z","timestamp":1657260372000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["SerpinB3 as a Pro-Inflammatory Mediator in the Progression of Experimental Non-Alcoholic Fatty Liver 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