NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis
Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment...
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| Veröffentlicht in: | EMBO reports 2022-11, Vol.23 (11), p.e54446-n/a |
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| creator | Kaufmann, Benedikt Leszczynska, Aleksandra Reca, Agustina Booshehri, Laela M Onyuru, Janset Tan, ZheHao Wree, Alexander Friess, Helmut Hartmann, Daniel Papouchado, Bettina Broderick, Lori Hoffman, Hal M Croker, Ben A Zhu, Yanfang Peipei Feldstein, Ariel E |
| description | Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil‐specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro‐inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro‐fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Synopsis
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Neutrophil‐specific NLRP3 activation leads to liver inflammation and lethal autoinflammation.
NLRP3 activation in neutrophils induces pro‐inflammatory cytokine and chemokine profiles in the liver.
NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death.
Neutrophil‐specific NLRP3 activation results in liver fibrosis associated with increased expression of pro‐fibrogenic genes.
Graphical Abstract
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis. |
| doi_str_mv | 10.15252/embr.202154446 |
| format | Article |
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Synopsis
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Neutrophil‐specific NLRP3 activation leads to liver inflammation and lethal autoinflammation.
NLRP3 activation in neutrophils induces pro‐inflammatory cytokine and chemokine profiles in the liver.
NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death.
Neutrophil‐specific NLRP3 activation results in liver fibrosis associated with increased expression of pro‐fibrogenic genes.
Graphical Abstract
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.</description><identifier>ISSN: 1469-221X</identifier><identifier>ISSN: 1469-3178</identifier><identifier>EISSN: 1469-3178</identifier><identifier>DOI: 10.15252/embr.202154446</identifier><identifier>PMID: 36194627</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animal models ; Animals ; Apoptosis ; Cell activation ; Cell death ; Chemokines ; Context ; Cytokines ; EMBO19 ; EMBO24 ; EMBO37 ; Fibrosis ; Gene expression ; Genes ; Hepatitis - genetics ; Hepatocytes ; Immune response ; Infiltration ; Inflammasomes ; Inflammasomes - genetics ; Inflammation ; Inflammation - metabolism ; Inflammatory response ; Interleukin-1beta - metabolism ; Leukocyte migration ; Leukocytes ; Leukocytes (neutrophilic) ; Liver ; Liver diseases ; liver inflammation ; macrophage ; Macrophages ; Mice ; Monocytes ; Mortality ; Mutants ; Myeloid cells ; neutrophil ; Neutrophils ; Neutrophils - metabolism ; NLR Family Pyrin Domain Containing 3 ; NLR Family, Pyrin Domain-Containing 3 Protein - genetics</subject><ispartof>EMBO reports, 2022-11, Vol.23 (11), p.e54446-n/a</ispartof><rights>The Author(s) 2022</rights><rights>2022 The Authors.</rights><rights>2022 EMBO</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5136-3e02cfff5c2b9ae4b926a56d12c0fe2fab86cf8182730d68ecc987278f9e6d913</citedby><cites>FETCH-LOGICAL-c5136-3e02cfff5c2b9ae4b926a56d12c0fe2fab86cf8182730d68ecc987278f9e6d913</cites><orcidid>0000-0003-3924-8487 ; 0000-0001-7202-3840</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638850/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638850/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,1427,27901,27902,41096,42165,45550,45551,46384,46808,51551,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.15252/embr.202154446$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36194627$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaufmann, Benedikt</creatorcontrib><creatorcontrib>Leszczynska, Aleksandra</creatorcontrib><creatorcontrib>Reca, Agustina</creatorcontrib><creatorcontrib>Booshehri, Laela M</creatorcontrib><creatorcontrib>Onyuru, Janset</creatorcontrib><creatorcontrib>Tan, ZheHao</creatorcontrib><creatorcontrib>Wree, Alexander</creatorcontrib><creatorcontrib>Friess, Helmut</creatorcontrib><creatorcontrib>Hartmann, Daniel</creatorcontrib><creatorcontrib>Papouchado, Bettina</creatorcontrib><creatorcontrib>Broderick, Lori</creatorcontrib><creatorcontrib>Hoffman, Hal M</creatorcontrib><creatorcontrib>Croker, Ben A</creatorcontrib><creatorcontrib>Zhu, Yanfang Peipei</creatorcontrib><creatorcontrib>Feldstein, Ariel E</creatorcontrib><title>NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis</title><title>EMBO reports</title><addtitle>EMBO Rep</addtitle><addtitle>EMBO Rep</addtitle><description>Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil‐specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro‐inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro‐fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Synopsis
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Neutrophil‐specific NLRP3 activation leads to liver inflammation and lethal autoinflammation.
NLRP3 activation in neutrophils induces pro‐inflammatory cytokine and chemokine profiles in the liver.
NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death.
Neutrophil‐specific NLRP3 activation results in liver fibrosis associated with increased expression of pro‐fibrogenic genes.
Graphical Abstract
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.</description><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell activation</subject><subject>Cell death</subject><subject>Chemokines</subject><subject>Context</subject><subject>Cytokines</subject><subject>EMBO19</subject><subject>EMBO24</subject><subject>EMBO37</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Hepatitis - genetics</subject><subject>Hepatocytes</subject><subject>Immune response</subject><subject>Infiltration</subject><subject>Inflammasomes</subject><subject>Inflammasomes - genetics</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Inflammatory response</subject><subject>Interleukin-1beta - metabolism</subject><subject>Leukocyte migration</subject><subject>Leukocytes</subject><subject>Leukocytes (neutrophilic)</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>liver inflammation</subject><subject>macrophage</subject><subject>Macrophages</subject><subject>Mice</subject><subject>Monocytes</subject><subject>Mortality</subject><subject>Mutants</subject><subject>Myeloid cells</subject><subject>neutrophil</subject><subject>Neutrophils</subject><subject>Neutrophils - metabolism</subject><subject>NLR Family Pyrin Domain Containing 3</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - genetics</subject><issn>1469-221X</issn><issn>1469-3178</issn><issn>1469-3178</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1DAUhSMEog9Ys0OR2HTBtPZ14tgskEpVoNLwUAUSO8txrjuuHGewk6n67zEzw7RFQqz8-s7RuT5F8YKSY1pDDSfYt_EYCNC6qir-qNinFZczRhvxeLsHoD_2ioOUrgkhtWzE02KPcSorDs1-oT_PL7-yUpvRrfTohlC6UAacxjgsF86nfOwmg6n0OC60L_U0Di5Yr_t-jb8uvVthLB_e6dCV1rVxSC49K55Y7RM-366Hxff359_OPs7mXz5cnJ3OZ6amjM8YEjDW2tpAKzVWrQSua95RMMQiWN0KbqygAhpGOi7QGCkaaISVyDtJ2WHxduO7nNoeO4NhjNqrZXS9jrdq0E49fAluoa6GlZKcCVGTbHC0NYjDzwnTqHqXDHqvAw5TUtAABQ4Vkxl99Rd6PUwx5PEyxaBqANaJTjaUyR-RItpdGErUuj71uz61qy8rXt6fYcf_6SsDbzbAjfN4-z8_df7p3eV9d7IRp6wLVxjvUv8r0C8JHbls</recordid><startdate>20221107</startdate><enddate>20221107</enddate><creator>Kaufmann, Benedikt</creator><creator>Leszczynska, Aleksandra</creator><creator>Reca, Agustina</creator><creator>Booshehri, Laela M</creator><creator>Onyuru, Janset</creator><creator>Tan, ZheHao</creator><creator>Wree, Alexander</creator><creator>Friess, Helmut</creator><creator>Hartmann, Daniel</creator><creator>Papouchado, Bettina</creator><creator>Broderick, Lori</creator><creator>Hoffman, Hal M</creator><creator>Croker, Ben A</creator><creator>Zhu, Yanfang Peipei</creator><creator>Feldstein, Ariel E</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>John Wiley and Sons Inc</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>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3924-8487</orcidid><orcidid>https://orcid.org/0000-0001-7202-3840</orcidid></search><sort><creationdate>20221107</creationdate><title>NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis</title><author>Kaufmann, Benedikt ; Leszczynska, Aleksandra ; Reca, Agustina ; Booshehri, Laela M ; Onyuru, Janset ; Tan, ZheHao ; Wree, Alexander ; Friess, Helmut ; Hartmann, Daniel ; Papouchado, Bettina ; Broderick, Lori ; Hoffman, Hal M ; Croker, Ben A ; Zhu, Yanfang Peipei ; Feldstein, Ariel E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5136-3e02cfff5c2b9ae4b926a56d12c0fe2fab86cf8182730d68ecc987278f9e6d913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cell activation</topic><topic>Cell death</topic><topic>Chemokines</topic><topic>Context</topic><topic>Cytokines</topic><topic>EMBO19</topic><topic>EMBO24</topic><topic>EMBO37</topic><topic>Fibrosis</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Hepatitis - genetics</topic><topic>Hepatocytes</topic><topic>Immune response</topic><topic>Infiltration</topic><topic>Inflammasomes</topic><topic>Inflammasomes - genetics</topic><topic>Inflammation</topic><topic>Inflammation - metabolism</topic><topic>Inflammatory response</topic><topic>Interleukin-1beta - metabolism</topic><topic>Leukocyte migration</topic><topic>Leukocytes</topic><topic>Leukocytes (neutrophilic)</topic><topic>Liver</topic><topic>Liver diseases</topic><topic>liver inflammation</topic><topic>macrophage</topic><topic>Macrophages</topic><topic>Mice</topic><topic>Monocytes</topic><topic>Mortality</topic><topic>Mutants</topic><topic>Myeloid cells</topic><topic>neutrophil</topic><topic>Neutrophils</topic><topic>Neutrophils - metabolism</topic><topic>NLR Family Pyrin Domain Containing 3</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaufmann, Benedikt</creatorcontrib><creatorcontrib>Leszczynska, Aleksandra</creatorcontrib><creatorcontrib>Reca, Agustina</creatorcontrib><creatorcontrib>Booshehri, Laela M</creatorcontrib><creatorcontrib>Onyuru, Janset</creatorcontrib><creatorcontrib>Tan, ZheHao</creatorcontrib><creatorcontrib>Wree, Alexander</creatorcontrib><creatorcontrib>Friess, Helmut</creatorcontrib><creatorcontrib>Hartmann, Daniel</creatorcontrib><creatorcontrib>Papouchado, Bettina</creatorcontrib><creatorcontrib>Broderick, Lori</creatorcontrib><creatorcontrib>Hoffman, Hal M</creatorcontrib><creatorcontrib>Croker, Ben A</creatorcontrib><creatorcontrib>Zhu, Yanfang Peipei</creatorcontrib><creatorcontrib>Feldstein, Ariel E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</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>EMBO reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Kaufmann, Benedikt</au><au>Leszczynska, Aleksandra</au><au>Reca, Agustina</au><au>Booshehri, Laela M</au><au>Onyuru, Janset</au><au>Tan, ZheHao</au><au>Wree, Alexander</au><au>Friess, Helmut</au><au>Hartmann, Daniel</au><au>Papouchado, Bettina</au><au>Broderick, Lori</au><au>Hoffman, Hal M</au><au>Croker, Ben A</au><au>Zhu, Yanfang Peipei</au><au>Feldstein, Ariel E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis</atitle><jtitle>EMBO reports</jtitle><stitle>EMBO Rep</stitle><addtitle>EMBO Rep</addtitle><date>2022-11-07</date><risdate>2022</risdate><volume>23</volume><issue>11</issue><spage>e54446</spage><epage>n/a</epage><pages>e54446-n/a</pages><issn>1469-221X</issn><issn>1469-3178</issn><eissn>1469-3178</eissn><abstract>Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil‐specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro‐inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro‐fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Synopsis
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.
Neutrophil‐specific NLRP3 activation leads to liver inflammation and lethal autoinflammation.
NLRP3 activation in neutrophils induces pro‐inflammatory cytokine and chemokine profiles in the liver.
NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death.
Neutrophil‐specific NLRP3 activation results in liver fibrosis associated with increased expression of pro‐fibrogenic genes.
Graphical Abstract
Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36194627</pmid><doi>10.15252/embr.202154446</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-3924-8487</orcidid><orcidid>https://orcid.org/0000-0001-7202-3840</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | Springer Nature OA Free Journals |
| subjects | Animal models Animals Apoptosis Cell activation Cell death Chemokines Context Cytokines EMBO19 EMBO24 EMBO37 Fibrosis Gene expression Genes Hepatitis - genetics Hepatocytes Immune response Infiltration Inflammasomes Inflammasomes - genetics Inflammation Inflammation - metabolism Inflammatory response Interleukin-1beta - metabolism Leukocyte migration Leukocytes Leukocytes (neutrophilic) Liver Liver diseases liver inflammation macrophage Macrophages Mice Monocytes Mortality Mutants Myeloid cells neutrophil Neutrophils Neutrophils - metabolism NLR Family Pyrin Domain Containing 3 NLR Family, Pyrin Domain-Containing 3 Protein - genetics |
| title | NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis |
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