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AuthorThiele, Jan R.dc.contributor.author
AuthorZeller, Johannesdc.contributor.author
AuthorKiefer, Jurijdc.contributor.author
AuthorBraig, Daviddc.contributor.author
AuthorKreuzaler, Sheenadc.contributor.author
AuthorLenz, Yvonnedc.contributor.author
AuthorPotempa, Lawrence A.dc.contributor.author
AuthorGrahammer, Floriandc.contributor.author
AuthorHuber, Tobias B.dc.contributor.author
AuthorHuber-Lang, M.dc.contributor.author
AuthorBannasch, Holgerdc.contributor.author
AuthorStark, G. Björndc.contributor.author
AuthorPeter, Karlheinzdc.contributor.author
AuthorEisenhardt, Steffen U.dc.contributor.author
Date of accession2021-12-07T11:58:31Zdc.date.accessioned
Available in OPARU since2021-12-07T11:58:31Zdc.date.available
Date of first publication2018-04-16dc.date.issued
AbstractIntroduction C-reactive protein circulates as a pentameric protein (pCRP). pCRP is a well-established diagnostic marker as plasma levels rise in response to tissue injury and inflammation. We recently described pro-inflammatory properties of CRP, which are mediated by conformational changes from pCRP to bioactive isoforms expressing pro-inflammatory neo-epitopes [pCRP* and monomeric C-reactive protein (mCRP)]. Here, we investigate the role of CRP isoforms in renal ischemia/reperfusion injury (IRI). Methods Rat kidneys in animals with and without intraperitoneally injected pCRP were subjected to IRI by the time of pCRP exposure and were subsequently analyzed for monocyte infiltration, caspase-3 expression, and tubular damage. Blood urea nitrogen (BUN) was analyzed pre-ischemia and post-reperfusion. CRP effects on leukocyte recruitment were investigated via intravital imaging of rat-striated muscle IRI. Localized conformational CRP changes were analyzed by immunohistochemistry using conformation specific antibodies. 1,6-bis(phosphocholine)-hexane (1,6-bisPC), which stabilizes CRP in its native pentameric form was used to validate CRP effects. Leukocyte activation was assessed by quantification of reactive oxygen species (ROS) induction by CRP isoforms ex vivo and in vitro through electron spin resonance spectroscopy. Signaling pathways were analyzed by disrupting lipid rafts with nystatin and subsequent ROS detection. In order to confirm the translational relevance of our findings, biopsies of microsurgical human free tissue transfers before and after IRI were examined by immunofluorescence for CRP deposition and co-localization of CD68+ leukocytes. Results The application of pCRP aggravates tissue damage in renal IRI. 1,6-bisPC reverses these effects via inhibition of the conformational change that leads to exposure of pro-inflammatory epitopes in CRP (pCRP* and mCRP). Structurally altered CRP induces leukocyte–endothelial interaction and induces ROS formation in leukocytes, the latter can be abrogated by blocking lipid raft-dependent signaling pathways with Nystatin. Stabilizing pCRP in its native pentameric state abrogates these pro-inflammatory effects. Importantly, these findings are confirmed in human IRI challenged muscle tissue. Conclusion These results suggest that CRP is a potent modulator of IRI. Stabilizing the native pCRP conformation represents a promising anti-inflammatory therapeutic strategy by attenuation of leukocyte recruitment and ROS formation, the primary pathomechanisms of IRI.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseCC BY 4.0 Internationaldc.rights
Link to license texthttps://creativecommons.org/licenses/by/4.0/dc.rights.uri
Keywordtherapeutic targetsdc.subject
Keywordconformational changedc.subject
Keywordtranslational medical researchdc.subject
Keywordleukocyte recruitmentdc.subject
Keywordrat modelsdc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHC-reactive proteindc.subject.mesh
MeSHIschemiadc.subject.mesh
MeSHReactive oxygen speciesdc.subject.mesh
MeSHLeukocytesdc.subject.mesh
TitleA conformational change in C-Reactive protein enhances leukocyte recruitment and reactive Oxygen species generation in Ischemia/Reperfusion injurydc.title
Resource typeWissenschaftlicher Artikeldc.type
SWORD Date2019-12-19T18:12:52Zdc.date.updated
VersionpublishedVersiondc.description.version
DOIhttp://dx.doi.org/10.18725/OPARU-40187dc.identifier.doi
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-40263-2dc.identifier.urn
GNDC-reaktives Proteindc.subject.gnd
GNDLeukozytdc.subject.gnd
InstitutionUKU. Institut für Klinische und Experimentelle Trauma-Immunologieuulm.affiliationSpecific
Peer reviewjauulm.peerReview
DCMI TypeCollectionuulm.typeDCMI
CategoryPublikationenuulm.category
In cooperation withRoosevelt Universityuulm.cooperation
In cooperation withUniversitätsklinikum Hamburg-Eppendorfuulm.cooperation
In cooperation withAlbert-Ludwigs-Universität Freiburguulm.cooperation
In cooperation withBaker Heart and Diabetes Instituteuulm.cooperation
DOI of original publication10.3389/fimmu.2018.00675dc.relation1.doi
Source - Title of sourceFrontiers in Immunologysource.title
Source - Place of publicationFrontiers Mediasource.publisher
Source - Volume9source.volume
Source - Year2018source.year
Source - Article number675source.articleNumber
Source - eISSN1664-3224source.identifier.eissn
Open AccessDOAJ Gold, Green Publisheduulm.OA
Bibliographyuulmuulm.bibliographie


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