Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury
Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates ho...
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| Veröffentlicht in: | The Journal of immunology (1950) 2017-05, Vol.198 (9), p.3588-3595 |
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| container_title | The Journal of immunology (1950) |
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| creator | Yue, Shi Zhou, Haoming Wang, Xuehao Busuttil, Ronald W Kupiec-Weglinski, Jerzy W Zhai, Yuan |
| description | Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. |
| doi_str_mv | 10.4049/jimmunol.1601428 |
| format | Article |
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Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1601428</identifier><identifier>PMID: 28289160</identifier><language>eng</language><publisher>United States: American Association of Immunologists</publisher><subject>Animals ; Antiretroviral drugs ; Bisphosphonates ; Cell activation ; Cells, Cultured ; Clodronic acid ; Clodronic Acid - pharmacology ; Depletion ; Disease Models, Animal ; Flow cytometry ; GTPase-Activating Proteins - antagonists & inhibitors ; GTPase-Activating Proteins - metabolism ; Humans ; Imidazoles - pharmacology ; Immune response ; Immunity ; Immunofluorescence ; Indoles - pharmacology ; Inflammation ; Inflammation - immunology ; Ischemia ; Kupffer cells ; Kupffer Cells - drug effects ; Kupffer Cells - immunology ; Kupffer Cells - pathology ; Liposomes ; Liver ; Liver - immunology ; Liver - pathology ; Macrophages ; Male ; Mice ; Mice, Inbred C57BL ; Necrosis ; Reperfusion ; Reperfusion Injury - immunology ; Signal Transduction ; T cell receptors</subject><ispartof>The Journal of immunology (1950), 2017-05, Vol.198 (9), p.3588-3595</ispartof><rights>Copyright © 2017 by The American Association of Immunologists, Inc.</rights><rights>Copyright American Association of Immunologists May 1, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-8b5aead6707dd1b54defb193880b8bbc1c64e6ba21b4fd9d020d184ef7a9b80e3</citedby><cites>FETCH-LOGICAL-c523t-8b5aead6707dd1b54defb193880b8bbc1c64e6ba21b4fd9d020d184ef7a9b80e3</cites><orcidid>0000-0001-8157-1531</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28289160$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yue, Shi</creatorcontrib><creatorcontrib>Zhou, Haoming</creatorcontrib><creatorcontrib>Wang, Xuehao</creatorcontrib><creatorcontrib>Busuttil, Ronald W</creatorcontrib><creatorcontrib>Kupiec-Weglinski, Jerzy W</creatorcontrib><creatorcontrib>Zhai, Yuan</creatorcontrib><title>Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.</description><subject>Animals</subject><subject>Antiretroviral drugs</subject><subject>Bisphosphonates</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Clodronic acid</subject><subject>Clodronic Acid - pharmacology</subject><subject>Depletion</subject><subject>Disease Models, Animal</subject><subject>Flow cytometry</subject><subject>GTPase-Activating Proteins - antagonists & inhibitors</subject><subject>GTPase-Activating Proteins - metabolism</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Immune response</subject><subject>Immunity</subject><subject>Immunofluorescence</subject><subject>Indoles - pharmacology</subject><subject>Inflammation</subject><subject>Inflammation - immunology</subject><subject>Ischemia</subject><subject>Kupffer cells</subject><subject>Kupffer Cells - drug effects</subject><subject>Kupffer Cells - immunology</subject><subject>Kupffer Cells - pathology</subject><subject>Liposomes</subject><subject>Liver</subject><subject>Liver - immunology</subject><subject>Liver - pathology</subject><subject>Macrophages</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Necrosis</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - immunology</subject><subject>Signal Transduction</subject><subject>T cell receptors</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUk1v1DAQjRCILoU7J2SJC5cU27Ed54JUtRQiLR-qlrNlx5OsV0kc7GSl_TX8Vbx0Wz5OnOYw772ZefOy7CXBFwyz6u3ODcMy-v6CCEwYlY-yFeEc50Jg8ThbYUxpTkpRnmXPYtxhjAWm7Gl2RiWVVeKssh9fg-_92IFFdWy2MDiNNsF1HYSIPkMT_OwadA1TD7PzI_It2rgYF8hvIToL44w-6YSatrqDiDYe3ejG9W7WM6B6bHs9DHr24YDq46qALpvZ7fUvLTeitdtD-D35FiYI7RKP3XrcLeHwPHvS6j7Ci1M9z77dvN9cfczXXz7UV5frvOG0mHNpuAZtRYlLa4nhzEJrSFVIiY00piGNYCCMpsSw1lYWU2yJZNCWujISQ3GevbvTnRYzgG3SYUH3agpu0OGgvHbq787otqrze8UZqZKbSeDNSSD47wvEWQ0uNtD3egS_REWS4ZJTzov_gJYlp4IRmqCv_4Hu_BLG5IRKY1mRfotFQuE7VHpEjAHah70JVsegqPugqFNQEuXVn_c-EO6TUfwEIzLATA</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Yue, Shi</creator><creator>Zhou, Haoming</creator><creator>Wang, Xuehao</creator><creator>Busuttil, Ronald W</creator><creator>Kupiec-Weglinski, Jerzy W</creator><creator>Zhai, Yuan</creator><general>American Association of Immunologists</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8157-1531</orcidid></search><sort><creationdate>20170501</creationdate><title>Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury</title><author>Yue, Shi ; Zhou, Haoming ; Wang, Xuehao ; Busuttil, Ronald W ; Kupiec-Weglinski, Jerzy W ; Zhai, Yuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-8b5aead6707dd1b54defb193880b8bbc1c64e6ba21b4fd9d020d184ef7a9b80e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antiretroviral drugs</topic><topic>Bisphosphonates</topic><topic>Cell activation</topic><topic>Cells, Cultured</topic><topic>Clodronic acid</topic><topic>Clodronic Acid - pharmacology</topic><topic>Depletion</topic><topic>Disease Models, Animal</topic><topic>Flow cytometry</topic><topic>GTPase-Activating Proteins - antagonists & inhibitors</topic><topic>GTPase-Activating Proteins - metabolism</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Immune response</topic><topic>Immunity</topic><topic>Immunofluorescence</topic><topic>Indoles - pharmacology</topic><topic>Inflammation</topic><topic>Inflammation - immunology</topic><topic>Ischemia</topic><topic>Kupffer cells</topic><topic>Kupffer Cells - drug effects</topic><topic>Kupffer Cells - immunology</topic><topic>Kupffer Cells - pathology</topic><topic>Liposomes</topic><topic>Liver</topic><topic>Liver - immunology</topic><topic>Liver - pathology</topic><topic>Macrophages</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Necrosis</topic><topic>Reperfusion</topic><topic>Reperfusion Injury - immunology</topic><topic>Signal Transduction</topic><topic>T cell receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yue, Shi</creatorcontrib><creatorcontrib>Zhou, Haoming</creatorcontrib><creatorcontrib>Wang, Xuehao</creatorcontrib><creatorcontrib>Busuttil, Ronald W</creatorcontrib><creatorcontrib>Kupiec-Weglinski, Jerzy W</creatorcontrib><creatorcontrib>Zhai, Yuan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yue, Shi</au><au>Zhou, Haoming</au><au>Wang, Xuehao</au><au>Busuttil, Ronald W</au><au>Kupiec-Weglinski, Jerzy W</au><au>Zhai, Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>198</volume><issue>9</issue><spage>3588</spage><epage>3595</epage><pages>3588-3595</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.</abstract><cop>United States</cop><pub>American Association of Immunologists</pub><pmid>28289160</pmid><doi>10.4049/jimmunol.1601428</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-8157-1531</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antiretroviral drugs Bisphosphonates Cell activation Cells, Cultured Clodronic acid Clodronic Acid - pharmacology Depletion Disease Models, Animal Flow cytometry GTPase-Activating Proteins - antagonists & inhibitors GTPase-Activating Proteins - metabolism Humans Imidazoles - pharmacology Immune response Immunity Immunofluorescence Indoles - pharmacology Inflammation Inflammation - immunology Ischemia Kupffer cells Kupffer Cells - drug effects Kupffer Cells - immunology Kupffer Cells - pathology Liposomes Liver Liver - immunology Liver - pathology Macrophages Male Mice Mice, Inbred C57BL Necrosis Reperfusion Reperfusion Injury - immunology Signal Transduction T cell receptors |
| title | Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury |
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