PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling
Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated w...
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| Veröffentlicht in: | The Journal of experimental medicine 2021-06, Vol.218 (6) |
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| container_title | The Journal of experimental medicine |
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| creator | Li, Jiwen Conrad, Catharina Mills, Tingting W Berg, Nathaniel K Kim, Boyun Ruan, Wei Lee, Jae W Zhang, Xu Yuan, Xiaoyi Eltzschig, Holger K |
| description | Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling. |
| doi_str_mv | 10.1084/jem.20210008 |
| format | Article |
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However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20210008</identifier><identifier>PMID: 33891683</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Animals ; Cardiovascular Biology ; Disease Models, Animal ; Female ; Innate immunity and inflammation ; Male ; Mice ; Mice, Inbred C57BL ; Myeloid Cells - metabolism ; Myocardial Infarction - metabolism ; Myocardial Ischemia - metabolism ; Myocardial Reperfusion Injury - metabolism ; Netrin-1 - metabolism ; Neutrophils - metabolism ; Receptor, Adenosine A2B - metabolism ; Signal Transduction - physiology</subject><ispartof>The Journal of experimental medicine, 2021-06, Vol.218 (6)</ispartof><rights>2021 Li et al.</rights><rights>2021 Li et al. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-ba27a2b930484e8c0975128d9699c58846aa882505d54373397689aacc81c5ff3</citedby><cites>FETCH-LOGICAL-c384t-ba27a2b930484e8c0975128d9699c58846aa882505d54373397689aacc81c5ff3</cites><orcidid>0000-0002-6041-4788 ; 0000-0002-2718-7923 ; 0000-0002-8595-860X ; 0000-0002-5676-6473 ; 0000-0003-2707-8927 ; 0000-0002-2898-6495 ; 0000-0002-7160-9169 ; 0000-0002-2568-2867 ; 0000-0002-4973-6647 ; 0000-0001-5731-3831</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33891683$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Jiwen</creatorcontrib><creatorcontrib>Conrad, Catharina</creatorcontrib><creatorcontrib>Mills, Tingting W</creatorcontrib><creatorcontrib>Berg, Nathaniel K</creatorcontrib><creatorcontrib>Kim, Boyun</creatorcontrib><creatorcontrib>Ruan, Wei</creatorcontrib><creatorcontrib>Lee, Jae W</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Yuan, Xiaoyi</creatorcontrib><creatorcontrib>Eltzschig, Holger K</creatorcontrib><title>PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling.</description><subject>Animals</subject><subject>Cardiovascular Biology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Innate immunity and inflammation</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myeloid Cells - metabolism</subject><subject>Myocardial Infarction - metabolism</subject><subject>Myocardial Ischemia - metabolism</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Netrin-1 - metabolism</subject><subject>Neutrophils - metabolism</subject><subject>Receptor, Adenosine A2B - metabolism</subject><subject>Signal Transduction - physiology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcuP0zAQhy0EYkvhxhn5yIEs41diX5DK8pQWFiE4W1Nn0nWVOF07qdT_nqB9CE5zmE-_eXyMvRRwLsDqt3saziVIAQD2EVsJo6FyRtnHbAUgZbU0mjP2rJQ9gNDa1E_ZmVLWidqqFcMf375XLeV4pJYnmnJMleA4TZRmnKjwgLmNGHgs4ZqGiFWmA-VuLnFMPKb9nE_8GJEPJ-rH2PLNh6ufG_mel7hL2Me0e86edNgXenFX1-z3p4-_Lr5Ul1efv15sLqugrJ6qLcoG5dYp0FaTDeAaI6RtXe1cMNbqGtFaacC0RqtGKdfU1iGGYEUwXafW7N1t7mHeDtQGSlPG3h9yHDCf_IjR_99J8drvxqO30DRiCVyz13cBebyZqUx-WI6mvsdE41y8NMLK5WsNLOibWzTksZRM3cMYAf6vFb9Y8fdWFvzVv6s9wPca1B_pYYiZ</recordid><startdate>20210607</startdate><enddate>20210607</enddate><creator>Li, Jiwen</creator><creator>Conrad, Catharina</creator><creator>Mills, Tingting W</creator><creator>Berg, Nathaniel K</creator><creator>Kim, Boyun</creator><creator>Ruan, Wei</creator><creator>Lee, Jae W</creator><creator>Zhang, Xu</creator><creator>Yuan, Xiaoyi</creator><creator>Eltzschig, Holger K</creator><general>Rockefeller University Press</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/0000-0002-6041-4788</orcidid><orcidid>https://orcid.org/0000-0002-2718-7923</orcidid><orcidid>https://orcid.org/0000-0002-8595-860X</orcidid><orcidid>https://orcid.org/0000-0002-5676-6473</orcidid><orcidid>https://orcid.org/0000-0003-2707-8927</orcidid><orcidid>https://orcid.org/0000-0002-2898-6495</orcidid><orcidid>https://orcid.org/0000-0002-7160-9169</orcidid><orcidid>https://orcid.org/0000-0002-2568-2867</orcidid><orcidid>https://orcid.org/0000-0002-4973-6647</orcidid><orcidid>https://orcid.org/0000-0001-5731-3831</orcidid></search><sort><creationdate>20210607</creationdate><title>PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling</title><author>Li, Jiwen ; Conrad, Catharina ; Mills, Tingting W ; Berg, Nathaniel K ; Kim, Boyun ; Ruan, Wei ; Lee, Jae W ; Zhang, Xu ; Yuan, Xiaoyi ; Eltzschig, Holger K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-ba27a2b930484e8c0975128d9699c58846aa882505d54373397689aacc81c5ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Cardiovascular Biology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Innate immunity and inflammation</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myeloid Cells - metabolism</topic><topic>Myocardial Infarction - metabolism</topic><topic>Myocardial Ischemia - metabolism</topic><topic>Myocardial Reperfusion Injury - metabolism</topic><topic>Netrin-1 - metabolism</topic><topic>Neutrophils - metabolism</topic><topic>Receptor, Adenosine A2B - metabolism</topic><topic>Signal Transduction - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Jiwen</creatorcontrib><creatorcontrib>Conrad, Catharina</creatorcontrib><creatorcontrib>Mills, Tingting W</creatorcontrib><creatorcontrib>Berg, Nathaniel K</creatorcontrib><creatorcontrib>Kim, Boyun</creatorcontrib><creatorcontrib>Ruan, Wei</creatorcontrib><creatorcontrib>Lee, Jae W</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Yuan, Xiaoyi</creatorcontrib><creatorcontrib>Eltzschig, Holger K</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>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Jiwen</au><au>Conrad, Catharina</au><au>Mills, Tingting W</au><au>Berg, Nathaniel K</au><au>Kim, Boyun</au><au>Ruan, Wei</au><au>Lee, Jae W</au><au>Zhang, Xu</au><au>Yuan, Xiaoyi</au><au>Eltzschig, Holger K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2021-06-07</date><risdate>2021</risdate><volume>218</volume><issue>6</issue><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1-elicited cardioprotection. 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| subjects | Animals Cardiovascular Biology Disease Models, Animal Female Innate immunity and inflammation Male Mice Mice, Inbred C57BL Myeloid Cells - metabolism Myocardial Infarction - metabolism Myocardial Ischemia - metabolism Myocardial Reperfusion Injury - metabolism Netrin-1 - metabolism Neutrophils - metabolism Receptor, Adenosine A2B - metabolism Signal Transduction - physiology |
| title | PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling |
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