Cell-specific regulatory effects of CXCR2 on cholestatic liver injury
The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injur...
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| Veröffentlicht in: | American journal of physiology: Gastrointestinal and liver physiology 2019-12, Vol.317 (6), p.G773-G783 |
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| creator | Konishi, Takanori Schuster, Rebecca M Goetzman, Holly S Caldwell, Charles C Lentsch, Alex B |
| description | The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2-/- mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2-/- mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2-/- mice showed significantly less neutrophil accumulation in those injured areas. CXCR2
and CXCR2
mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2
mice suffered higher liver injury than CXCR2
and CXCR2
; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2
and CXCR2
) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury. |
| doi_str_mv | 10.1152/ajpgi.00080.2019 |
| format | Article |
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and CXCR2
mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2
mice suffered higher liver injury than CXCR2
and CXCR2
; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2
and CXCR2
) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.</description><identifier>ISSN: 0193-1857</identifier><identifier>EISSN: 1522-1547</identifier><identifier>DOI: 10.1152/ajpgi.00080.2019</identifier><identifier>PMID: 31604030</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Bile ; Bile ducts ; Cell Migration Inhibition ; Cell Movement - drug effects ; Chemokine CXCL1 - metabolism ; Chemokine CXCL2 - metabolism ; Chemokines ; Chimeras ; Cholestasis - complications ; CXC chemokines ; CXCR2 protein ; Disease Models, Animal ; Fibrosis ; Hepatic Infarction - drug therapy ; Hepatic Infarction - etiology ; Hepatic Infarction - metabolism ; Hepatocytes ; Leukocytes (neutrophilic) ; Liver ; Liver - metabolism ; Liver - pathology ; Mice ; Necrosis ; Neutrophils ; Neutrophils - physiology ; Phenotypes ; Phenylurea Compounds - pharmacology ; Protective Agents - pharmacology ; Receptors, Interleukin-8B - antagonists & inhibitors ; Receptors, Interleukin-8B - metabolism ; Therapeutic applications</subject><ispartof>American journal of physiology: Gastrointestinal and liver physiology, 2019-12, Vol.317 (6), p.G773-G783</ispartof><rights>Copyright American Physiological Society Dec 2019</rights><rights>Copyright © 2019 the American Physiological Society 2019 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-f23f0e4ee7b79b670aa6376a9b24ecf01784ccb7cce3f5f521d6e0126b6b58fb3</citedby><cites>FETCH-LOGICAL-c424t-f23f0e4ee7b79b670aa6376a9b24ecf01784ccb7cce3f5f521d6e0126b6b58fb3</cites><orcidid>0000-0002-4403-8313</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,3040,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31604030$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Konishi, Takanori</creatorcontrib><creatorcontrib>Schuster, Rebecca M</creatorcontrib><creatorcontrib>Goetzman, Holly S</creatorcontrib><creatorcontrib>Caldwell, Charles C</creatorcontrib><creatorcontrib>Lentsch, Alex B</creatorcontrib><title>Cell-specific regulatory effects of CXCR2 on cholestatic liver injury</title><title>American journal of physiology: Gastrointestinal and liver physiology</title><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><description>The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2-/- mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2-/- mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2-/- mice showed significantly less neutrophil accumulation in those injured areas. CXCR2
and CXCR2
mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2
mice suffered higher liver injury than CXCR2
and CXCR2
; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2
and CXCR2
) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.</description><subject>Animals</subject><subject>Bile</subject><subject>Bile ducts</subject><subject>Cell Migration Inhibition</subject><subject>Cell Movement - drug effects</subject><subject>Chemokine CXCL1 - metabolism</subject><subject>Chemokine CXCL2 - metabolism</subject><subject>Chemokines</subject><subject>Chimeras</subject><subject>Cholestasis - complications</subject><subject>CXC chemokines</subject><subject>CXCR2 protein</subject><subject>Disease Models, Animal</subject><subject>Fibrosis</subject><subject>Hepatic Infarction - drug therapy</subject><subject>Hepatic Infarction - etiology</subject><subject>Hepatic Infarction - metabolism</subject><subject>Hepatocytes</subject><subject>Leukocytes (neutrophilic)</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Mice</subject><subject>Necrosis</subject><subject>Neutrophils</subject><subject>Neutrophils - physiology</subject><subject>Phenotypes</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Protective Agents - pharmacology</subject><subject>Receptors, Interleukin-8B - antagonists & inhibitors</subject><subject>Receptors, Interleukin-8B - metabolism</subject><subject>Therapeutic applications</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctLJDEQxoO4rKPu3ZM0ePHSs5X39EVYGl8gLCy74C2kY2XM0NMZk25h_nvjE9dTQdWvPuqrj5AjCnNKJftpV5tlmAPAAuYMaLNDZqXNaiqF3iWz0uE1XUi9R_ZzXhVOMkq_kz1OFQjgMCPnLfZ9nTfogg-uSricejvGtK3Qe3RjrqKv2tv2D6viULn72GMe7VjQPjxiqsKwmtL2kHzzts_4460ekH8X53_bq_rm9-V1--umdoKJsfaMe0CBqDvddEqDtYprZZuOCXQeqF4I5zrtHHIvfTn2TiFQpjrVyYXv-AE5e9XdTN0a7xwOY7K92aSwtmlrog3m_8kQ7s0yPhrVKCYaWQRO3wRSfJiKFbMO2ZUX2AHjlA3jIEEqLlhBT76gqzilodgrFG00VayBQsEr5VLMOaH_OIaCec7IvGRkXjIyzxmVlePPJj4W3kPhT1Z3jjs</recordid><startdate>20191201</startdate><enddate>20191201</enddate><creator>Konishi, Takanori</creator><creator>Schuster, Rebecca M</creator><creator>Goetzman, Holly S</creator><creator>Caldwell, Charles C</creator><creator>Lentsch, Alex B</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4403-8313</orcidid></search><sort><creationdate>20191201</creationdate><title>Cell-specific regulatory effects of CXCR2 on cholestatic liver injury</title><author>Konishi, Takanori ; Schuster, Rebecca M ; Goetzman, Holly S ; Caldwell, Charles C ; Lentsch, Alex B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-f23f0e4ee7b79b670aa6376a9b24ecf01784ccb7cce3f5f521d6e0126b6b58fb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Bile</topic><topic>Bile ducts</topic><topic>Cell Migration Inhibition</topic><topic>Cell Movement - drug effects</topic><topic>Chemokine CXCL1 - metabolism</topic><topic>Chemokine CXCL2 - metabolism</topic><topic>Chemokines</topic><topic>Chimeras</topic><topic>Cholestasis - complications</topic><topic>CXC chemokines</topic><topic>CXCR2 protein</topic><topic>Disease Models, Animal</topic><topic>Fibrosis</topic><topic>Hepatic Infarction - drug therapy</topic><topic>Hepatic Infarction - etiology</topic><topic>Hepatic Infarction - metabolism</topic><topic>Hepatocytes</topic><topic>Leukocytes (neutrophilic)</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Mice</topic><topic>Necrosis</topic><topic>Neutrophils</topic><topic>Neutrophils - physiology</topic><topic>Phenotypes</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Protective Agents - pharmacology</topic><topic>Receptors, Interleukin-8B - antagonists & inhibitors</topic><topic>Receptors, Interleukin-8B - metabolism</topic><topic>Therapeutic applications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Konishi, Takanori</creatorcontrib><creatorcontrib>Schuster, Rebecca M</creatorcontrib><creatorcontrib>Goetzman, Holly S</creatorcontrib><creatorcontrib>Caldwell, Charles C</creatorcontrib><creatorcontrib>Lentsch, Alex B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Konishi, Takanori</au><au>Schuster, Rebecca M</au><au>Goetzman, Holly S</au><au>Caldwell, Charles C</au><au>Lentsch, Alex B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell-specific regulatory effects of CXCR2 on cholestatic liver injury</atitle><jtitle>American journal of physiology: Gastrointestinal and liver physiology</jtitle><addtitle>Am J Physiol Gastrointest Liver Physiol</addtitle><date>2019-12-01</date><risdate>2019</risdate><volume>317</volume><issue>6</issue><spage>G773</spage><epage>G783</epage><pages>G773-G783</pages><issn>0193-1857</issn><eissn>1522-1547</eissn><abstract>The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2-/- mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2-/- mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2-/- mice showed significantly less neutrophil accumulation in those injured areas. CXCR2
and CXCR2
mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2
mice suffered higher liver injury than CXCR2
and CXCR2
; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2
and CXCR2
) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>31604030</pmid><doi>10.1152/ajpgi.00080.2019</doi><orcidid>https://orcid.org/0000-0002-4403-8313</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Physiological Society Paid; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Bile Bile ducts Cell Migration Inhibition Cell Movement - drug effects Chemokine CXCL1 - metabolism Chemokine CXCL2 - metabolism Chemokines Chimeras Cholestasis - complications CXC chemokines CXCR2 protein Disease Models, Animal Fibrosis Hepatic Infarction - drug therapy Hepatic Infarction - etiology Hepatic Infarction - metabolism Hepatocytes Leukocytes (neutrophilic) Liver Liver - metabolism Liver - pathology Mice Necrosis Neutrophils Neutrophils - physiology Phenotypes Phenylurea Compounds - pharmacology Protective Agents - pharmacology Receptors, Interleukin-8B - antagonists & inhibitors Receptors, Interleukin-8B - metabolism Therapeutic applications |
| title | Cell-specific regulatory effects of CXCR2 on cholestatic liver injury |
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