Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.

Carmen M Dickinson-Copeland,Michael Wilson,Shailesh Singh,Vincent Bond,Jonathan K Stiles,Adel Driss,Mingli Liu,Daniel Oduro,Kingsley Badu,Felix Botchway,Winston Anderson,Ben Gyan,Hassana Salifu,Methode Bacanamwo,Nana O Wilson,Andrew A Adjei

doi:10.1371/journal.pone.0142328

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.

Highlights

Plasmodium falciparum infections are responsible for about 283 million malaria cases and 584,000 deaths annually, primarily in Sub Saharan Africa [1]
We hypothesized that endothelial progenitor cell (EPC) depletion during malaria pathogenesis is a function of hemeinduced apoptosis mediated by CXCL10 induction and Toll-like receptor (TLR) activation
We have previously shown that free heme is a potent apoptotic factor as well as inducer of the pro-inflammatory chemokine CXCL10 in microvasculature (HBVEC) in vitro and in murine models of experimental cerebral malaria (ECM) [11, 30]

Summary

Introduction

Plasmodium falciparum infections are responsible for about 283 million malaria cases and 584,000 deaths annually, primarily in Sub Saharan Africa [1]. Malaria mortality is associated with exaggerated host responses to inflammatory factors such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), free heme, C-X-C motif chemokine 10 (CXCL10) and parasite-derived cytotoxins [6,7,8,9,10,11]. Previous studies indicate that increased serum levels of free heme and CXCL10 limited the ability of the host to repair and regenerate damaged blood-brain barrier (BBB) components during development of severe malaria pathogenesis and were predictive of poor prognosis of severe malaria [14]. CD34+ hematopoietic stem and progenitor cells (CD34+-HSPC) are blood-cell precursors of T- and B-lymphocytes, which are potently activated by microvascular damage and alterations in chemokine/cytokine expression [19,20,21]. By-products of this signaling pathway result in increased expression of the heme-degrading enzyme, heme-oxygenase-1 (HO-1), CXCL10 and adhesion molecules such as vascular and intercellular cell adhesion molecules [12, 23, 24]

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