{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:16:58Z","timestamp":1792671418635,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts of cell-free heme intravascularly and consumption of the protective heme-scavenger proteins in plasma. The liberation of heme has been linked to the activation of inflammatory systems, including the complement system, through alternative pathway activation. Here, we investigated the impact of heme on the regulatory function of the complement system. Heme dose-dependently inhibited factor I-mediated degradation of soluble and surface-bound C3b, when incubated in plasma or buffer with complement regulatory proteins. Inhibition occurred with factor H and soluble complement receptor 1 as co-factors, and the mechanism was linked to the direct heme-interaction with factor I. The heme-scavenger protein hemopexin was the main contaminant in purified factor I preparations. This led us to identify that hemopexin formed a complex with factor I in normal human plasma. These complexes were significantly reduced during acute vasoocclusive pain crisis in patients with sickle cell disease, but the complexes were normalized at their baseline outpatient clinic visit. Hemopexin exposed a protective function of factor I activity\n                    <jats:italic>in vitro<\/jats:italic>\n                    , but only when it was present before the addition of heme. In conclusion, we present a mechanistic explanation of how heme promotes uncontrolled complement alternative pathway amplification by interfering with the regulatory capacity of factor I. Reduced levels of hemopexin and hemopexin-factor I complexes during an acute hemolytic crisis is a risk factor for heme-mediated factor I inhibition.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.901876","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T10:26:17Z","timestamp":1658485577000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation"],"prefix":"10.3389","volume":"13","author":[{"given":"Alexandra","family":"Gerogianni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Dimitrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Zarantonello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Poillerat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satheesh","family":"Chonat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Sandholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin E.","family":"McAdam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina N.","family":"Ekdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom E.","family":"Mollnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Mohlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubka T.","family":"Roumenina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per H.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89741","article-title":"Intravascular Hemolysis and the Pathophysiology of Sickle Cell Disease","volume":"127","author":"Kato","year":"2017","journal-title":"J Clin Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-489245","article-title":"Complement Activation by Heme as a Secondary Hit for Atypical Hemolytic Uremic Syndrome","volume":"122","author":"Frimat","year":"2013","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00312.2016","article-title":"There Is Blood in the Water: Hemolysis, Hemoglobin, and Heme in Acute Lung Injury","volume":"311","author":"Gaggar","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-11-451229","article-title":"Hemolysis and Free Hemoglobin Revisited: Exploring Hemoglobin and Hemin Scavengers as a Novel Class of Therapeutic Proteins","volume":"121","author":"Schaer","year":"2013","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.healun.2013.08.019","article-title":"Hemolysis in Left Ventricular Assist Device: A Retrospective Analysis of Outcomes","volume":"33","author":"Ravichandran","year":"2014","journal-title":"J Heart Lung Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/CRD.0b013e31819f1a83","article-title":"Hemolysis Associated With Prosthetic Heart Valves: A Review","volume":"17","author":"Shapira","year":"2009","journal-title":"Cardiol Rev"},{"key":"B7","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.coi.2015.11.006","article-title":"Red Alert: Labile Heme Is an Alarmin","volume":"38","author":"Soares","year":"2016","journal-title":"Curr Opin Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.tibtech.2012.10.003","article-title":"Haptoglobin: The Hemoglobin Detoxifier in Plasma","volume":"31","author":"Alayash","year":"2013","journal-title":"Trends Biotechnol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.10.030","article-title":"Oxidized Hemoglobin Forms Contribute to Nlrp3 Inflammasome-Driven Il-1beta Production Upon Intravascular Hemolysis","volume":"1865","author":"Nyakundi","year":"2019","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-495887","article-title":"Heme Triggers Tlr4 Signaling Leading to Endothelial Cell Activation and Vaso-Occlusion in Murine Sickle Cell Disease","volume":"123","author":"Belcher","year":"2014","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1814797116","article-title":"P-Selectin Drives Complement Attack on Endothelium During Intravascular Hemolysis in Tlr-4\/Heme-Dependent Manner","volume":"116","author":"Merle","year":"2019","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/toxins11110660","article-title":"Hemolysis Derived Products Toxicity and Endothelium: Model of the Second Hit","volume":"11","author":"Frimat","year":"2019","journal-title":"Toxins (Basel)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03177.x","article-title":"Heme Induces Endothelial Tissue Factor Expression: Potential Role in Hemostatic Activation in Patients With Hemolytic Anemia","volume":"6","author":"Setty","year":"2008","journal-title":"J Thromb Haemost"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2016.01.004","article-title":"Heme: Modulator of Plasma Systems in Hemolytic Diseases","volume":"22","author":"Roumenina","year":"2016","journal-title":"Trends Mol Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1661666","article-title":"The Interaction of the Factor Viii\/Von Willebrand Factor Complex With Hematin","volume":"56","author":"Green","year":"1986","journal-title":"Thromb Haemost"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-01-198309","article-title":"Receptor Targeting of Hemoglobin Mediated by the Haptoglobins: Roles Beyond Heme Scavenging","volume":"114","author":"Nielsen","year":"2009","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nature11369","article-title":"Structure of the Haptoglobin-Haemoglobin Complex","volume":"489","author":"Andersen","year":"2012","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/15216540500380871","article-title":"Hemoglobin and Heme Scavenging","volume":"57","author":"Ascenzi","year":"2005","journal-title":"IUBMB Life"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201402218","article-title":"Regulatory Fe(Ii\/Iii) Heme: The Reconstruction of a Molecule's Biography","volume":"15","author":"Kuhl","year":"2014","journal-title":"Chembiochem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nm1202-799","article-title":"Cell-Free Hemoglobin Limits Nitric Oxide Bioavailability in Sickle-Cell Disease","volume":"8","author":"Reiter","year":"2002","journal-title":"Nat Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I - Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2019.05.003","volume":"224","author":"Lachmann","year":"2019","journal-title":"Immunobiology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02627.x","article-title":"The Quantitative Role of Alternative Pathway Amplification in Classical Pathway Induced Terminal Complement Activation","volume":"138","author":"Harboe","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.605691","article-title":"A Revised Mechanism for the Activation of Complement C3 to C3b: A Molecular Explanation of a Disease-Associated Polymorphism","volume":"290","author":"Rodriguez","year":"2015","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.097212","article-title":"Analysis of Binding Sites on Complement Factor I That Are Required for Its Activity","volume":"285","author":"Nilsson","year":"2010","journal-title":"J Biol Chem"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1172\/jci.insight.96910","article-title":"Intravascular Hemolysis Activates Complement Via Cell-Free Heme and Heme-Loaded Microvesicles","volume":"3","author":"Merle","year":"2018","journal-title":"JCI Insight"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900047","article-title":"Complement Component C5 and Tlr Molecule Cd14 Mediate Heme-Induced Thromboinflammation in Human Blood","volume":"203","author":"Thomas","year":"2019","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1995.1131","article-title":"Complement Activation During Painful Crisis in Sickle Cell Anemia","volume":"76","author":"Mold","year":"1995","journal-title":"Clin Immunol Immunopathol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01492.x","article-title":"Complement Driven Innate Immune Response to Malaria: Fuelling Severe Malarial Diseases","volume":"12","author":"Silver","year":"2010","journal-title":"Cell Microbiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.1016\/S0021-9258(19)69557-8","article-title":"Large Scale Isolation of Functionally Active Components of the Human Complement System","volume":"256","author":"Hammer","year":"1981","journal-title":"J Biol Chem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1084\/jem.122.2.277","article-title":"Isolation of Beta If-Globulin From Human Serum and Its Characterization as the Fifth Component of Complement","volume":"122","author":"Nilsson","year":"1965","journal-title":"J Exp Med"},{"key":"B32","volume-title":"Immunochemistry in Practice","author":"Alan Johnstone","year":"1996"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-78952-1_20","article-title":"Compstatin: A Complement Inhibitor on Its Way to Clinical Application","volume":"632","author":"Ricklin","year":"2008","journal-title":"Adv Exp Med Biol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102167108","article-title":"Structural Basis for Complement Factor I Control and Its Disease-Associated Sequence Polymorphisms","volume":"108","author":"Roversi","year":"2011","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3427","article-title":"Regulator-Dependent Mechanisms of C3b Processing by Factor I Allow Differentiation of Immune Responses","volume":"24","author":"Xue","year":"2017","journal-title":"Nat Struct Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24433","article-title":"Protein Docking Using Case-Based Reasoning","volume":"81","author":"Ghoorah","year":"2013","journal-title":"Proteins"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.206136","article-title":"Heme Interacts With C1q and Inhibits the Classical Complement Pathway","volume":"286","author":"Roumenina","year":"2011","journal-title":"J Biol Chem"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(90)90252-b","article-title":"Introduction of Sulfhydryl Groups Into Proteins at Carboxyl Sites","volume":"1038","author":"Lin","year":"1990","journal-title":"Biochim Biophys Acta"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2013.05.221","article-title":"An International Serum Standard for Application in Assays to Detect Human Complement Activation Products","volume":"56","author":"Bergseth","year":"2013","journal-title":"Mol Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00146","article-title":"Heme as a Target for Therapeutic Interventions","volume":"8","author":"Immenschuh","year":"2017","journal-title":"Front Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/prot.22747","article-title":"Heme Proteins\u2013Diversity in Structural Characteristics, Function, and Folding","volume":"78","author":"Smith","year":"2010","journal-title":"Proteins"},{"key":"B42","doi-asserted-by":"publisher","first-page":"16893","DOI":"10.1038\/s41598-019-53231-0","article-title":"Structural Insights Into Heme Binding to Il-36alpha Proinflammatory Cytokine","volume":"9","author":"Wissbrock","year":"2019","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00115","article-title":"Heme on Innate Immunity and Inflammation","volume":"5","author":"Dutra","year":"2014","journal-title":"Front Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.8.5543","article-title":"Hematin Promotes Complement Alternative Pathway-Mediated Deposition of C3 Activation Fragments on Human Erythrocytes: Potential Implications for the Pathogenesis of Anemia in Malaria","volume":"179","author":"Pawluczkowycz","year":"2007","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00530","article-title":"Assessment of the Role of C3(H2o) in the Alternative Pathway","volume":"11","author":"Fromell","year":"2020","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jcm11030630","article-title":"Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence","volume":"11","author":"Gentinetta","year":"2022","journal-title":"J Clin Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e0196455","DOI":"10.1371\/journal.pone.0196455","article-title":"Haptoglobin and Hemopexin Inhibit Vaso-Occlusion and Inflammation in Murine Sickle Cell Disease: Role of Heme Oxygenase-1 Induction","volume":"13","author":"Belcher","year":"2018","journal-title":"PLoS One"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23683","article-title":"Factors Associated With Survival in a Contemporary Adult Sickle Cell Disease Cohort","volume":"89","author":"Elmariah","year":"2014","journal-title":"Am J Hematol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e1915374","DOI":"10.1001\/jamanetworkopen.2019.15374","article-title":"Estimated Life Expectancy and Income of Patients With Sickle Cell Disease Compared With Those Without Sickle Cell Disease","volume":"2","author":"Lubeck","year":"2019","journal-title":"JAMA Netw Open"},{"key":"B50","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1182\/blood-2021-154132","article-title":"Complement Activation During Vaso-Occlusive Pain Crisis in Pediatric Sickle Cell Disease","volume":"138","author":"Yoo","year":"2021","journal-title":"Blood"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25384","article-title":"Critical Role of C5a in Sickle Cell Disease","volume":"94","author":"Vercellotti","year":"2019","journal-title":"Am J Hematol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.901876\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T10:26:22Z","timestamp":1658485582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.901876\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,22]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2022.901876"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.901876","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,22]]},"article-number":"901876"}}