Dickinson-Copeland Carmen M, Wilson Nana O, Liu Mingli, Driss Adel, Salifu Hassana, Adjei Andrew A, Wilson Michael, Gyan Ben, Oduro Daniel, Badu Kingsley, Botchway Felix, Anderson Winston, Bond Vincent, Bacanamwo Methode, Singh Shailesh, Stiles Jonathan K
Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
Department of Pathology, Korle-Bu Teaching Hospital, University of Ghana Medical School, Accra, Ghana.
PLoS One. 2015 Nov 10;10(11):e0142328. doi: 10.1371/journal.pone.0142328. eCollection 2015.
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.
恶性疟原虫感染若不治疗可导致微血管功能障碍、脑性脑病甚至死亡。我们之前已经表明，疟疾患者血清中的高浓度游离血红素和C-X-C基序趋化因子10（CXCL10）可诱导微血管内皮细胞和神经元细胞凋亡，进而导致血管功能障碍、血脑屏障（BBB）损伤和死亡。内皮祖细胞（EPC）是微血管内皮细胞的前体，部分负责受损血脑屏障内皮的修复和再生。研究表明，严重疟疾患者体内的EPC数量减少，但其介导这一现象的机制尚不清楚。Toll样受体可识别由细菌和寄生虫等病原体产生的多种病原体相关分子模式。我们检验了这样一个假设：疟疾发病过程中EPC数量减少是由CXCL10诱导和Toll样受体（TLR）激活介导的血红素诱导凋亡所致。与非疟疾患者相比，疟疾患者血浆中的血红素和CXCL10浓度升高。疟疾患者的EPC数量显著减少（P < 0.02），且体内TLR4表达显著升高。这些发现在体外EPC前体细胞中得到了证实；研究确定血红素诱导的凋亡和CXCL10表达是由TLR4介导的。我们得出结论，血清血红素增加介导了疟疾发病过程中EPC数量的减少。
