{"id":{"repo_id":"aachen","oai_identifier":"oai:publications.rwth-aachen.de:51502"},"canonical_url":"https://search.dev.ndltd.org/etd/aachen/oai:publications.rwth-aachen.de:51502","repository":{"repo_id":"aachen","name":"RWTH Aachen University","base_url":"https://publications.rwth-aachen.de/oai2d"},"display":{"title":"Role of monocyte subsets in chronic liver injury and liver fibrosis","abstract":"Monocytes are key players of the innate immune system and crucially modulate tissue inflammation after injury. Mammalian monocytes consist of two principle subsets that display different chemokine receptor expression levels. In humans, the classical monocyte CD14++CD16- subset expresses CCR2, CD64, CD62L and low levels of the fractalkine receptor CX3CR1, whereas the non-classical CD14lowCD16+ monocyte subset expresses high levels of CX3CR1 and lack CCR2. Their counterparts in mice are CCR2+Gr-1hi and CCR2-Gr-1low monocytes, respectively. Liver fibrosis is the consequence of chronic liver inflammation, which is characterized by the accumulation of extracellular matrix proteins such as collagen-I. Patients with liver fibrosis are at high risk of developing liver cirrhosis or hepatocellular carcinoma. The functional contribution of monocyte subsets to chronic liver inflammation and liver fibrosis are as of yet not well understood. This study addresses the role of monocyte subsets in liver inflammation and fibrosis, using the well established model of carbon tetrachloride (CCl4)-induced toxic liver injury in C57Bl/6 mice. Acute CCl4-mediated liver injury resulted in the massive infiltration of Gr-1hi monocytes into the liver of WT animals, which peaked at 24h and 48h. Intrahepatic recruitment of the Gr-1hi monocyte subset was markedly reduced in Ccr2-/- and Ccr2-/-Ccr6-/- mice, when compared to WT animals in the model of acute as well as chronic liver injury. In chronic CCl4-mediated liver injury, detailed analysis showed that the reduced amount of CCR2+Gr-1hi monocytes in the inflamed liver coincides with reduced activation of hepatic stellate cells, less collagen-I accumulation and reduced liver fibrosis in the Ccr2-/- and Ccr2-/-Ccr6-/- mice. Adoptive transfer of WT monocytes into the Ccr2-/-Ccr6-/- or WT animals massively aggravates hepatic fibrosis. Isolated liver-derived Gr-1hi monocytes, but not control cells such as bone marrow-derived monocytes, CD8+ T-cells or CD19+ B-cells, directly activate hepatic stellate cells in vitro. Inhibition of TGFbeta1 in a co-culture blocked the HSC activation potential of liver-derived inflammatory monocytes, suggesting that liver infiltrating Gr-1hi monocytes activate hepatic stellate cells in a TGFβ1-dependent manner. These findings provide evidences, that the chemokine receptor CCR2 is involved in recruiting the Gr-1hi monocytes to the inflamed liver and suggest an important role of these monocyte subsets for liver fibrosis progression by activating hepatic stellate cells via TGFbeta1. Thus, modulating Gr-1hi monocyte infiltration during chronic liver inflammation could possibly be a novel therapeutic approach to control liver fibrosis in humans.","abstract_html":"Monocytes are key players of the innate immune system and crucially modulate tissue inflammation after injury. Mammalian monocytes consist of two principle subsets that display different chemokine receptor expression levels. In humans, the classical monocyte CD14++CD16- subset expresses CCR2, CD64, CD62L and low levels of the fractalkine receptor CX3CR1, whereas the non-classical CD14lowCD16+ monocyte subset expresses high levels of CX3CR1 and lack CCR2. Their counterparts in mice are CCR2+Gr-1hi and CCR2-Gr-1low monocytes, respectively. Liver fibrosis is the consequence of chronic liver inflammation, which is characterized by the accumulation of extracellular matrix proteins such as collagen-I. Patients with liver fibrosis are at high risk of developing liver cirrhosis or hepatocellular carcinoma. The functional contribution of monocyte subsets to chronic liver inflammation and liver fibrosis are as of yet not well understood. This study addresses the role of monocyte subsets in liver inflammation and fibrosis, using the well established model of carbon tetrachloride (CCl4)-induced toxic liver injury in C57Bl/6 mice. Acute CCl4-mediated liver injury resulted in the massive infiltration of Gr-1hi monocytes into the liver of WT animals, which peaked at 24h and 48h. Intrahepatic recruitment of the Gr-1hi monocyte subset was markedly reduced in Ccr2-/- and Ccr2-/-Ccr6-/- mice, when compared to WT animals in the model of acute as well as chronic liver injury. In chronic CCl4-mediated liver injury, detailed analysis showed that the reduced amount of CCR2+Gr-1hi monocytes in the inflamed liver coincides with reduced activation of hepatic stellate cells, less collagen-I accumulation and reduced liver fibrosis in the Ccr2-/- and Ccr2-/-Ccr6-/- mice. Adoptive transfer of WT monocytes into the Ccr2-/-Ccr6-/- or WT animals massively aggravates hepatic fibrosis. Isolated liver-derived Gr-1hi monocytes, but not control cells such as bone marrow-derived monocytes, CD8+ T-cells or CD19+ B-cells, directly activate hepatic stellate cells in vitro. Inhibition of TGFbeta1 in a co-culture blocked the HSC activation potential of liver-derived inflammatory monocytes, suggesting that liver infiltrating Gr-1hi monocytes activate hepatic stellate cells in a TGFβ1-dependent manner. These findings provide evidences, that the chemokine receptor CCR2 is involved in recruiting the Gr-1hi monocytes to the inflamed liver and suggest an important role of these monocyte subsets for liver fibrosis progression by activating hepatic stellate cells via TGFbeta1. Thus, modulating Gr-1hi monocyte infiltration during chronic liver inflammation could possibly be a novel therapeutic approach to control liver fibrosis in humans.","abstract_has_math":false,"creators":["Karlmark, Karlin Raja"],"institution":"Publikationsserver der RWTH Aachen University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Tacke, Frank"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2009,"date_issued":"2009","date_published":"2009","updated_at":"2026-07-30T19:40:42Z","subjects":["info:eu-repo/classification/ddc/570","Monozyt","Leberfibrose","Biowissenschaften, Biologie","monocyte","liver fibrosis"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113790%22"],"render_values":[{"text":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113790%22","href":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113790%22","code":true}]}]},"links":{"outbound_url":"https://publications.rwth-aachen.de/record/51502","outbound_label":"Repository record","outbound_source":"dc:identifier"},"source_record":{"url":"https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51502","prefix":"oai_dc"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Tacke, Frank"]},{"key":"dc:creator","label":"Author","values":["Karlmark, Karlin Raja"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:coverage","label":"Dc Coverage","values":["DE"]},{"key":"dc:date","label":"Dc Date","values":["2009"]},{"key":"dc:publisher","label":"Institution","values":["Publikationsserver der RWTH Aachen University"]},{"key":"dc:relation","label":"Dc Relation","values":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-30942"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis","info:eu-repo/semantics/publishedVersion"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["info:eu-repo/classification/ddc/570","Monozyt","Leberfibrose","Biowissenschaften, Biologie","monocyte","liver fibrosis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/record/51502","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113790%22"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Monocytes are key players of the innate immune system and crucially modulate tissue inflammation after injury. Mammalian monocytes consist of two principle subsets that display different chemokine receptor expression levels. In humans, the classical monocyte CD14++CD16- subset expresses CCR2, CD64, CD62L and low levels of the fractalkine receptor CX3CR1, whereas the non-classical CD14lowCD16+ monocyte subset expresses high levels of CX3CR1 and lack CCR2. Their counterparts in mice are CCR2+Gr-1hi and CCR2-Gr-1low monocytes, respectively. Liver fibrosis is the consequence of chronic liver inflammation, which is characterized by the accumulation of extracellular matrix proteins such as collagen-I. Patients with liver fibrosis are at high risk of developing liver cirrhosis or hepatocellular carcinoma. The functional contribution of monocyte subsets to chronic liver inflammation and liver fibrosis are as of yet not well understood. This study addresses the role of monocyte subsets in liver inflammation and fibrosis, using the well established model of carbon tetrachloride (CCl4)-induced toxic liver injury in C57Bl/6 mice. Acute CCl4-mediated liver injury resulted in the massive infiltration of Gr-1hi monocytes into the liver of WT animals, which peaked at 24h and 48h. Intrahepatic recruitment of the Gr-1hi monocyte subset was markedly reduced in Ccr2-/- and Ccr2-/-Ccr6-/- mice, when compared to WT animals in the model of acute as well as chronic liver injury. In chronic CCl4-mediated liver injury, detailed analysis showed that the reduced amount of CCR2+Gr-1hi monocytes in the inflamed liver coincides with reduced activation of hepatic stellate cells, less collagen-I accumulation and reduced liver fibrosis in the Ccr2-/- and Ccr2-/-Ccr6-/- mice. Adoptive transfer of WT monocytes into the Ccr2-/-Ccr6-/- or WT animals massively aggravates hepatic fibrosis. Isolated liver-derived Gr-1hi monocytes, but not control cells such as bone marrow-derived monocytes, CD8+ T-cells or CD19+ B-cells, directly activate hepatic stellate cells in vitro. Inhibition of TGFbeta1 in a co-culture blocked the HSC activation potential of liver-derived inflammatory monocytes, suggesting that liver infiltrating Gr-1hi monocytes activate hepatic stellate cells in a TGFβ1-dependent manner. These findings provide evidences, that the chemokine receptor CCR2 is involved in recruiting the Gr-1hi monocytes to the inflamed liver and suggest an important role of these monocyte subsets for liver fibrosis progression by activating hepatic stellate cells via TGFbeta1. Thus, modulating Gr-1hi monocyte infiltration during chronic liver inflammation could possibly be a novel therapeutic approach to control liver fibrosis in humans."]},{"key":"dc:source","label":"Dc Source","values":["Aachen : Publikationsserver der RWTH Aachen University XIV, 97 Bl. : Ill., graph. Darst. (2009). = Aachen, Techn. Hochsch., Diss., 2009"]},{"key":"dc:title","label":"Title","values":["Role of monocyte subsets in chronic liver injury and liver fibrosis"]}]}],"canonical_facts":{"dc:contributor":["Tacke, Frank"],"dc:coverage":["DE"],"dc:creator":["Karlmark, Karlin Raja"],"dc:date":["2009"],"dc:description":["Monocytes are key players of the innate immune system and crucially modulate tissue inflammation after injury. Mammalian monocytes consist of two principle subsets that display different chemokine receptor expression levels. In humans, the classical monocyte CD14++CD16- subset expresses CCR2, CD64, CD62L and low levels of the fractalkine receptor CX3CR1, whereas the non-classical CD14lowCD16+ monocyte subset expresses high levels of CX3CR1 and lack CCR2. Their counterparts in mice are CCR2+Gr-1hi and CCR2-Gr-1low monocytes, respectively. Liver fibrosis is the consequence of chronic liver inflammation, which is characterized by the accumulation of extracellular matrix proteins such as collagen-I. Patients with liver fibrosis are at high risk of developing liver cirrhosis or hepatocellular carcinoma. The functional contribution of monocyte subsets to chronic liver inflammation and liver fibrosis are as of yet not well understood. This study addresses the role of monocyte subsets in liver inflammation and fibrosis, using the well established model of carbon tetrachloride (CCl4)-induced toxic liver injury in C57Bl/6 mice. Acute CCl4-mediated liver injury resulted in the massive infiltration of Gr-1hi monocytes into the liver of WT animals, which peaked at 24h and 48h. Intrahepatic recruitment of the Gr-1hi monocyte subset was markedly reduced in Ccr2-/- and Ccr2-/-Ccr6-/- mice, when compared to WT animals in the model of acute as well as chronic liver injury. In chronic CCl4-mediated liver injury, detailed analysis showed that the reduced amount of CCR2+Gr-1hi monocytes in the inflamed liver coincides with reduced activation of hepatic stellate cells, less collagen-I accumulation and reduced liver fibrosis in the Ccr2-/- and Ccr2-/-Ccr6-/- mice. Adoptive transfer of WT monocytes into the Ccr2-/-Ccr6-/- or WT animals massively aggravates hepatic fibrosis. Isolated liver-derived Gr-1hi monocytes, but not control cells such as bone marrow-derived monocytes, CD8+ T-cells or CD19+ B-cells, directly activate hepatic stellate cells in vitro. Inhibition of TGFbeta1 in a co-culture blocked the HSC activation potential of liver-derived inflammatory monocytes, suggesting that liver infiltrating Gr-1hi monocytes activate hepatic stellate cells in a TGFβ1-dependent manner. These findings provide evidences, that the chemokine receptor CCR2 is involved in recruiting the Gr-1hi monocytes to the inflamed liver and suggest an important role of these monocyte subsets for liver fibrosis progression by activating hepatic stellate cells via TGFbeta1. Thus, modulating Gr-1hi monocyte infiltration during chronic liver inflammation could possibly be a novel therapeutic approach to control liver fibrosis in humans."],"dc:identifier":["https://publications.rwth-aachen.de/record/51502","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113790%22"],"dc:language":["eng"],"dc:publisher":["Publikationsserver der RWTH Aachen University"],"dc:relation":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-30942"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:source":["Aachen : Publikationsserver der RWTH Aachen University XIV, 97 Bl. : Ill., graph. Darst. (2009). = Aachen, Techn. Hochsch., Diss., 2009"],"dc:subject":["info:eu-repo/classification/ddc/570","Monozyt","Leberfibrose","Biowissenschaften, Biologie","monocyte","liver fibrosis"],"dc:title":["Role of monocyte subsets in chronic liver injury and liver fibrosis"],"dc:type":["info:eu-repo/semantics/doctoralThesis","info:eu-repo/semantics/publishedVersion"]},"updated_at":"2026-07-30T19:40:42Z"}