Transcriptional and Histochemical Signatures of Bone Marrow Mononuclear Cell-Mediated Resolution of Synovitis

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dc.contributor.authorMenarim, Bruno C.en
dc.contributor.authorAli, Hossam El-Sheikhen
dc.contributor.authorLoux, Shavahn C.en
dc.contributor.authorScoggin, Kirsten E.en
dc.contributor.authorKalbfleisch, Theodore S.en
dc.contributor.authorMacLeod, James N.en
dc.contributor.authorDahlgren, Linda A.en
dc.date.accessioned2022-06-16T20:44:45Zen
dc.date.available2022-06-16T20:44:45Zen
dc.date.issued2021-12-08en
dc.description.abstractOsteoarthritis (OA) may result from impaired ability of synovial macrophages to resolve joint inflammation. Increasing macrophage counts in inflamed joints through injection with bone marrow mononuclear cells (BMNC) induces lasting resolution of synovial inflammation. To uncover mechanisms by which BMNC may affect resolution, in this study, differential transcriptional signatures of BMNC in response to normal (SF) and inflamed synovial fluid (ISF) were analyzed. We demonstrate the temporal behavior of coexpressed gene networks associated with traits from related in vivo and in vitro studies. We also identified activated and inhibited signaling pathways and upstream regulators, further determining their protein expression in the synovium of inflamed joints treated with BMNC or DPBS controls. BMNC responded to ISF with an early pro-inflammatory response characterized by a short spike in the expression of a NF-ƙB- and mitogenrelated gene network. This response was associated with sustained increased expression of two gene networks comprising known drivers of resolution (IL-10, IGF-1, PPARG, isoprenoid biosynthesis). These networks were common to SF and ISF, but more highly expressed in ISF. Most highly activated pathways in ISF included the mevalonate pathway and PPAR-𝛄 signaling, with pro-resolving functional annotations that improve mitochondrial metabolism and deactivate NF-ƙB signaling. Lower expression of mevalonate kinase and phospho-PPAR-𝛄 in synovium from inflamed joints treated with BMNC, and equivalent IL-1β staining between BMNC- and DPBS-treated joints, associates with accomplished resolution in BMNC-treated joints and emphasize the intricate balance of pro- and anti-inflammatory mechanisms required for resolution. Combined, our data suggest that BMNC-mediated resolution is characterized by constitutively expressed homeostatic mechanisms, whose expression are enhanced following inflammatory stimulus. These mechanisms translate into macrophage proliferation optimizing their capacity to counteract inflammatory damage and improving their general and mitochondrial metabolism to endure oxidative stress while driving tissue repair. Such effect is largely achieved through the synthesis of several lipids that mediate recovery of homeostasis. Our study reveals candidate mechanisms by which BMNC provide lasting improvement in patients with OA and suggests further investigation on the effects of PPAR-𝛄 signaling enhancement for the treatment of arthritic conditions.en
dc.description.sponsorshipThis study was supported by the Grayson-Jockey Club Research Foundation and the Virginia-Maryland College of Veterinary Medicine Internal Research Competition. BM received graduate assistantship support from the Interdisciplinary Graduate Education Program at Virginia Tech, the Virginia-Maryland College of Veterinary Medicine and the College of Agriculture, Food and Environment at the University of Kentucky.en
dc.description.versionPublished versionen
dc.format.extent21 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMenarim BC, El-Sheikh Ali H, Loux SC, Scoggin KE, Kalbfleisch TS, MacLeod JN and Dahlgren LA (2021) Transcriptional and Histochemical Signatures of Bone Marrow Mononuclear Cell-Mediated Resolution of Synovitis. Front. Immunol. 12:734322. doi: 10.3389/fimmu.2021.734322en
dc.identifier.doihttps://doi.org/10.3389/fimmu.2021.734322en
dc.identifier.urihttp://hdl.handle.net/10919/110810en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmacrophageen
dc.subjectarthritisen
dc.subjectmevalonate pathwayen
dc.subjectoxidative stressen
dc.subjectjoint therapyen
dc.titleTranscriptional and Histochemical Signatures of Bone Marrow Mononuclear Cell-Mediated Resolution of Synovitisen
dc.title.serialFrontiers in Immunologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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