title: Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.
abstract: Plasmodium falciparum infection can cause microvascular dysfunction, cerebral encephalopathy and death if untreated. We have previously shown that high concentrations of free heme, and C-X-C motif chemokine 10 (CXCL10) in sera of malaria patients induce apoptosis in microvascular endothelial and neuronal cells contributing to vascular dysfunction, blood-brain barrier (BBB) damage and mortality. Endothelial progenitor cells (EPC) are microvascular endothelial cell precursors partly responsible for repair and regeneration of damaged BBB endothelium. Studies have shown that EPC's are depleted in severe malaria patients, but the mechanisms mediating this phenomenon are unknown. Toll-like receptors recognize a wide variety of pathogen-associated molecular patterns generated by pathogens such as bacteria and parasites. We tested the hypothesis that EPC depletion during malaria pathogenesis is a function of heme-induced apoptosis mediated by CXCL10 induction and toll-like receptor (TLR) activation. Heme and CXCL10 concentrations in plasma obtained from malaria patients were elevated compared with non-malaria subjects. EPC numbers were significantly decreased in malaria patients (P < 0.02) and TLR4 expression was significantly elevated in vivo. These findings were confirmed in EPC precursors in vitro; where it was determined that heme-induced apoptosis and CXCL10 expression was TLR4-mediated. We conclude that increased serum heme mediates depletion of EPC during malaria pathogenesis.
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Dickinson-Copeland
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Nana O
authors.initials: NO
authors.lastname: Wilson
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mingli
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Adel
authors.initials: A
authors.lastname: Driss
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Hassana
authors.initials: H
authors.lastname: Salifu
authors.affiliation: Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana.|Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Adjei
authors.affiliation: Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Ben
authors.initials: B
authors.lastname: Gyan
authors.affiliation: Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Daniel
authors.initials: D
authors.lastname: Oduro
authors.affiliation: Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
authors.forename: Kingsley
authors.initials: K
authors.lastname: Badu
authors.affiliation: Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana.
authors.forename: Felix
authors.initials: F
authors.lastname: Botchway
authors.affiliation: Department of Biology, Howard University, Washington, DC, United States of America.
authors.forename: Winston
authors.initials: W
authors.lastname: Anderson
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bond
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Methode
authors.initials: M
authors.lastname: Bacanamwo
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Stiles
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000276:immunology*; D016022:Case-Control Studies; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006418:Heme / Q000502:physiology*; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood* / Q000276:immunology; D008297:Male; D013234:Stem Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D006418:Heme