{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:53:01Z","timestamp":1775627581177,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontierspartnerships.org"],"crossmark-restriction":true},"short-container-title":["Transpl. Int."],"abstract":"<jats:p>\n                    Donor-derived cell-free DNA (dd-cfDNA) is a biomarker for rejection after organ transplantation. We hypothesized that high release of cfDNA immediately after liver transplant also has a biologic role in inflammation in ischemia and reperfusion injury (IRI). To investigate this concept, C57BL\/6 mice were subjected to 90\u00a0min\n                    <jats:italic>in situ<\/jats:italic>\n                    liver ischemia. After 6\u00a0h reperfusion, cfDNA was purified from serum and used to stimulate macrophages\n                    <jats:italic>in vitro<\/jats:italic>\n                    , which resulted in production of high levels of inflammatory cytokines TNF\u03b1 and IL-6, and chemokine CXCL10. Enzymatic degradation of cfDNA by DNase I inhibited these inflammatory responses (e.g., TNF\u03b1: DNase I 48.1 \u00b1 37.4 vs. untreated 1,030 \u00b1 206\u00a0pg\/mL, p = 0.0001). cfDNA from netosis-deficient PAD4KO mice was found to be equally pro-inflammatory compared to wild type cfDNA (TNF\u03b1: PAD4KO 1048 \u00b1 199 vs. wild-type 1,162 \u00b1 150\u00a0pg\/mL, p = 0.64), indicating its mechanism is not dependent on neutrophils undergoing netosis. Next, a single dose of DNase I was added to the perfusate during rat liver normothermic machine perfusion (NMP) to significantly reduce perfusate cfDNA levels (384 \u00b1 132 to 129 \u00b1 18\u00a0ng\/mL, p = 0.026). In conclusion, our data suggest that cfDNA can have pro-inflammatory effects during liver IRI beyond being a biomarker. DNase I may be a promising therapeutic intervention during NMP to reduce the graft\u2019s inflammatory propensity prior to implantation.\n                  <\/jats:p>","DOI":"10.3389\/ti.2026.15340","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:10:22Z","timestamp":1775625022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond a Biomarker: Investigations of a Proinflammatory Role for Cell-Free DNA in Liver Transplant Ischemia and Reperfusion"],"prefix":"10.3389","volume":"39","author":[{"given":"Mike","family":"Schnepppfister","sequence":"first","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhong","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tori","family":"Huey","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hesham","family":"El-Shewy","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichu","family":"Kao","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph R.","family":"Scalea","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas A.","family":"Morinelli","sequence":"additional","affiliation":[{"name":"The Lee Patterson Allen Transplant Immunobiology Laboratory, Department of Surgery, Medical University of South Carolina","place":["Charleston, SC, United 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