Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation
Identifieur interne : 000732 ( Main/Exploration ); précédent : 000731; suivant : 000733Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation
Auteurs : Lars Henrik Mariero ; May-Kristin Torp ; Christina Mathisen Heiestad ; Anton Baysa ; Yuchuan Li ; Guro Valen ; Jarle Vaage ; K Re-Olav Stensl KkenSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2019.
Abstract
Cellular debris causes sterile inflammation after myocardial infarction. Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage‐associated‐molecular‐pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll‐like receptor 9 (TLR9).
We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia‐reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA.
Expression of the pro‐inflammatory cytokines IL‐1β and TNFα were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia‐reoxygenation. Blocking the RNA/DNA binding protein nucleolin with midkine reduced expression of IL‐1β/TNFα and the nucleolin inhibitor AS1411 reduced interleukin‐6 release in adult mouse cardiomyocytes. mtDNA bound 10‐fold stronger than nDNA to nucleolin. In HEK293‐NF‐κB reporter cells, mtDNA induced NF‐κB activity in normoxia, while CpG‐DNA and hypoxia‐reoxygenation, synergistically induced TLR9‐dependent NF‐κB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG‐DNA. Inhibition of endocytosis did not reduce CpG‐DNA uptake in cardiomyocytes.
mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia‐reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation.
This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit
Url:
DOI: 10.1111/bph.14830
PubMed: 31412132
PubMed Central: 6887679
Affiliations:
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id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Torp, May Ristin" sort="Torp, May Ristin" uniqKey="Torp M" first="May-Kristin" last="Torp">May-Kristin Torp</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Heiestad, Christina Mathisen" sort="Heiestad, Christina Mathisen" uniqKey="Heiestad C" first="Christina Mathisen" last="Heiestad">Christina Mathisen Heiestad</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Baysa, Anton" sort="Baysa, Anton" uniqKey="Baysa A" first="Anton" last="Baysa">Anton Baysa</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Li, Yuchuan" sort="Li, Yuchuan" uniqKey="Li Y" first="Yuchuan" last="Li">Yuchuan Li</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Valen, Guro" sort="Valen, Guro" uniqKey="Valen G" first="Guro" last="Valen">Guro Valen</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Vaage, Jarle" sort="Vaage, Jarle" uniqKey="Vaage J" first="Jarle" last="Vaage">Jarle Vaage</name><affiliation><nlm:aff id="bph14830-aff-0003"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Stensl Kken, K Re Lav" sort="Stensl Kken, K Re Lav" uniqKey="Stensl Kken K" first="K Re-Olav" last="Stensl Kken">K Re-Olav Stensl Kken</name><affiliation><nlm:aff id="bph14830-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14830-aff-0002"></nlm:aff></affiliation></author></analytic><series><title level="j">British Journal of Pharmacology</title><idno type="ISSN">0007-1188</idno><idno type="eISSN">1476-5381</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="bph14830-sec-0001"><title>Background and purpose</title><p>Cellular debris causes sterile inflammation after myocardial infarction. Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage‐associated‐molecular‐pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll‐like receptor 9 (TLR9).</p></sec><sec id="bph14830-sec-0002"><title>Experimental Approach</title><p>We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia‐reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA.</p></sec><sec id="bph14830-sec-0003"><title>Key results</title><p>Expression of the pro‐inflammatory cytokines IL‐1β and TNFα were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia‐reoxygenation. Blocking the RNA/DNA binding protein nucleolin with midkine reduced expression of IL‐1β/TNFα and the nucleolin inhibitor AS1411 reduced interleukin‐6 release in adult mouse cardiomyocytes. mtDNA bound 10‐fold stronger than nDNA to nucleolin. In HEK293‐NF‐κB reporter cells, mtDNA induced NF‐κB activity in normoxia, while CpG‐DNA and hypoxia‐reoxygenation, synergistically induced TLR9‐dependent NF‐κB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG‐DNA. Inhibition of endocytosis did not reduce CpG‐DNA uptake in cardiomyocytes.</p></sec><sec id="bph14830-sec-0004"><title>Conclusion and implications</title><p>mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia‐reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation.</p></sec><sec id="bph14830-sec-1000"><title>Linked Articles</title><p>This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit <ext-link ext-link-type="uri" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc</ext-link></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Olson, J M O" uniqKey="Olson J">J. M. O. 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