After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89300 |
| Date | 19 March 2024 |
| Creators | Klapproth, Erik, Witt, Anke, Klose, Pauline, Wiedemann, Johanna, Vavilthota, Nikitha, Künzel, Stephan R., Kämmerer, Susanne, Günscht, Mario, Sprott, David, Lesche, Mathias, Rost, Fabian, Dahl, Andreas, Rauch, Erik, Kattner, Lars, Weber, Silvio, Mirtschink, Peter, Kopaliani, Irakli, Guan, Kaomei, Lorenz, Kristina, Saftig, Paul, Wagner, Michael, El-Armouche, Ali |
| Publisher | Nature Publishing Group |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2041-1723, 7648, 10.1038/s41467-022-35331-0, info:eu-repo/grantAgreement/Deutsche Forschungsgemeinschaft/Internationale Graduiertenkollegs/288034826//GRK 2251: Immunologische und zellbasierte Strategien bei metabolischen Erkrankungen, info:eu-repo/grantAgreement/Deutsche Forschungsgemeinschaft/SFB 877: Proteolyse als regulatorisches Ereignis in der Pathophysiologie/125440785//A03 - Analyse der Zellbiologie und der Modulation von ADAM10, info:eu-repo/grantAgreement/Deutsche Forschungsgemeinschaft/SFB 1525: Kardio-immune Schnittstellen/453989101//B03 - Die Bedeutung der nukleären ERK 1/2 Signaltransduktion in inflammatorischen kardiovaskulären Erkrankungen, info:eu-repo/grantAgreement/Deutsche Forschungsgemeinschaft/TRR 296: Lokale Kontrolle der Schilddrüsenhormonwirkung (LocoTact)/424957847//P10 - Lokale TH-Wirkung in der akuten und chronischen kardialen Ischämie |
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