{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:51:49Z","timestamp":1761709909917,"version":"build-2065373602"},"reference-count":28,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB841 B1 and SFB841 B9"],"award-info":[{"award-number":["SFB841 B1 and SFB841 B9"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-\u03b2) is pivotal for scarring and fibrosis induction and progression. TGF-\u03b2 signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-\u03b2-signalling pathway, rendering cells that express high levels of it resistant to TGF-\u03b2-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl4)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smadfl\/fl mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl4 induces severe liver injury, with elevated serum alanine transaminase (ALT)\/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl4-treated animals. In summary, our results suggest that, during long-term application of CCl4, Smad7 expression in myeloid cells and its potential effects on the TGF-\u03b2-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.<\/jats:p>","DOI":"10.3390\/ijms222111575","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"11575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl4 Exposure in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Ludmilla","family":"Unrau","sequence":"first","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Department of Virology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Endig","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane","family":"Goltz","sequence":"additional","affiliation":[{"name":"Institute for Hematopathology, Fangdieckstrasse 75a, 22547 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Sprezyna","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Ulrich","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Hagenstein","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"Geers","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina","family":"Kaftan","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas Carl","family":"Heukamp","sequence":"additional","affiliation":[{"name":"Institute for Hematopathology, Fangdieckstrasse 75a, 22547 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisa","family":"Tiegs","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Diehl","sequence":"additional","affiliation":[{"name":"Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"},{"name":"Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20190103","DOI":"10.1084\/jem.20190103","article-title":"Transforming growth factor-\u03b2 in tissue fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-\u03b2\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1093\/ndt\/gfn699","article-title":"Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice","volume":"24","author":"Chung","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.1478-3231.2009.02011.x","article-title":"Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice","volume":"29","author":"Latella","year":"2009","journal-title":"Liver Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/334260a0","article-title":"Deactivation of macrophages by transforming growth factor-beta","volume":"334","author":"Tsunawaki","year":"1988","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1161\/CIRCRESAHA.119.315069","article-title":"Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation","volume":"125","author":"Chen","year":"2019","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/hep.26351","article-title":"C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice","volume":"58","author":"Chu","year":"2013","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaav5183","DOI":"10.1126\/scisignal.aav5183","article-title":"Specificity, versatility, and control of TGF-\u03b2 family signaling","volume":"12","author":"Derynck","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1093\/jmcb\/mjz057","article-title":"VprBP mitigates TGF-\u03b2 and Activin signaling by promoting Smurf1-mediated type I receptor degradation","volume":"12","author":"Li","year":"2020","journal-title":"J. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/pr.2016.18","article-title":"Smad7 interrupts TGF-\u03b2 signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis","volume":"79","author":"MohanKumar","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1111\/imm.12690","article-title":"High Smad7 sustains inflammatory cytokine response in refractory coeliac disease","volume":"150","author":"Sedda","year":"2017","journal-title":"Immunology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3389\/fphys.2012.00053","article-title":"Differential Regulation of TGF-\u03b2\/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries","volume":"3","author":"Yoshida","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1111\/j.1582-4934.2008.00262.x","article-title":"Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice","volume":"12","author":"Hamzavi","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e294","DOI":"10.1038\/oncsis.2016.85","article-title":"Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice","volume":"6","author":"Feng","year":"2017","journal-title":"Oncogenesis"},{"doi-asserted-by":"crossref","unstructured":"Endig, J., Unrau, L., Sprezyna, P., Rading, S., Karsak, M., Goltz, D., Heukamp, L., Tiegs, G., and Diehl, L. (2019). Acute liver injury after CCl4 administration is independent of Smad7 expression in myeloid cells. Int. J. Mol. Sci., 20.","key":"ref_16","DOI":"10.3390\/ijms20225528"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri3623","article-title":"Liver fibrosis and repair: Immune regulation of wound healing in a solid organ","volume":"14","author":"Pellicoro","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3389\/fonc.2018.00357","article-title":"Transforming Growth Factor-\u03b2-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis","volume":"8","author":"Fabregat","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1038\/s41385-018-0041-4","article-title":"Cytomegalovirus promotes intestinal macrophage-mediated mucosal inflammation through induction of Smad7","volume":"11","author":"Dennis","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1053\/j.gastro.2008.04.038","article-title":"Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage","volume":"135","author":"Dooley","year":"2008","journal-title":"Gastroenterology"},{"doi-asserted-by":"crossref","unstructured":"Zhu, L., Wang, L., Wang, X., Luo, X., Yang, L., Zhang, R., Yin, H., Xie, D., Pan, Y., and Chen, Y. (2011). Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury. PLoS ONE, 6.","key":"ref_21","DOI":"10.1371\/journal.pone.0017415"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/emmm.201000085","article-title":"Regulation of liver regeneration by growth factors and cytokines","volume":"2","author":"Speicher","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s00204-014-1436-y","article-title":"Inhibition of TGF\u03b2 type I receptor activity facilitates liver regeneration upon acute CCl4 intoxication in mice","volume":"90","author":"Karkampouna","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.jhep.2013.12.025","article-title":"Macrophage heterogeneity in liver injury and fibrosis","volume":"60","author":"Tacke","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.3389\/fimmu.2019.02670","article-title":"Contribution of Macrophage Efferocytosis to Liver Homeostasis and Disease","volume":"10","author":"Horst","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/hep.30925","article-title":"The unexpected role of neutrophils for resolving liver inflammation by transmitting microRNA-223 to macrophages","volume":"71","author":"Guillot","year":"2019","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9914","DOI":"10.1073\/pnas.1304046110","article-title":"Eosinophils secrete IL-4 to facilitate liver regeneration","volume":"110","author":"Goh","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1002\/hep.26196","article-title":"Eosinophils mediate the pathogenesis of halothane-induced liver injury in mice","volume":"57","author":"Proctor","year":"2013","journal-title":"Hepatology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11575\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:24:26Z","timestamp":1760167466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,27]]},"references-count":28,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111575"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111575","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,10,27]]}}}