McGilvray I D, Serghides L, Kapus A, Rotstein O D, Kain K C
Departments of Medicine and Surgery, University of Toronto, Toronto, Ontario, Canada.
Blood. 2000 Nov 1;96(9):3231-40.
Plasmodium falciparum is the most lethal form of malaria and is increasing both in incidence and in its resistance to antimalarial agents. An improved understanding of the mechanisms of malarial clearance may facilitate the development of new therapeutic interventions. We postulated that the scavenger receptor CD36, an important factor in cytoadherence of P falciparum-parasitized erythrocytes (PEs), might also play a role in monocyte- and macrophage-mediated malarial clearance. Exposure of nonopsonized PEs to Fc receptor-blocked monocytes resulted in significant PE phagocytosis, accompanied by intense clustering of CD36 around the PEs. Phagocytosis was blocked 60% to 70% by monocyte pretreatment with monoclonal anti-CD36 antibodies but not by antibodies to alpha(v)beta(3), thrombospondin, intercellular adhesion molecule-1, or platelet/endothelial cell adhesion molecule-1. Antibody-induced CD36 cross-linking did result in the early increase of surface CD11b expression, but there was no increase in, or priming for, tumor necrosis factor (TNF)-alpha secretion following either CD36 cross-linking or PE phagocytosis. CD36 clustering does support intracellular signaling: Antibody-induced cross-linking initiated intracellular tyrosine phosphorylation as well as extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Both broad-spectrum tyrosine kinase inhibition (genistein) and selective ERK and p38 MAPK inhibition (PD98059 and SB203580, respectively) reduced PE uptake to almost the same extent as CD36 blockade. Thus, CD36-dependent binding and signaling appears to be crucial for the nonopsonic clearance of PEs and does not appear to contribute to the increase in TNF-alpha that is prognostic of poor outcome in clinical malaria.
恶性疟原虫是疟疾最致命的形式，其发病率及对抗疟药物的耐药性均在增加。更好地了解疟疾清除机制可能有助于开发新的治疗干预措施。我们推测，清道夫受体CD36是恶性疟原虫寄生红细胞（PEs）细胞黏附的重要因素，它可能在单核细胞和巨噬细胞介导的疟疾清除中也发挥作用。未调理的PEs与Fc受体阻断的单核细胞接触会导致显著的PE吞噬作用，同时PEs周围会出现强烈的CD36聚集。用抗CD36单克隆抗体对单核细胞进行预处理可使吞噬作用阻断60%至70%，但抗α(v)β(3)、血小板反应蛋白、细胞间黏附分子-1或血小板/内皮细胞黏附分子-1的抗体则无此作用。抗体诱导的CD36交联确实导致表面CD11b表达早期增加，但在CD36交联或PE吞噬后，肿瘤坏死因子（TNF）-α分泌没有增加或引发。CD36聚集确实支持细胞内信号传导：抗体诱导的交联引发细胞内酪氨酸磷酸化以及细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）磷酸化。广谱酪氨酸激酶抑制（染料木黄酮）以及选择性ERK和p38 MAPK抑制（分别为PD98059和SB203580）使PE摄取减少的程度几乎与CD36阻断相同。因此，CD36依赖性结合和信号传导似乎对PEs的非调理清除至关重要，且似乎与临床疟疾中预后不良的TNF-α增加无关。
