RESUMEN
Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.
Asunto(s)
Barrera Hematoencefálica/parasitología , Malaria Cerebral/parasitología , Receptor EphA2/metabolismo , Adolescente , Animales , Barrera Hematoencefálica/metabolismo , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Malaria Cerebral/genética , Malaria Cerebral/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasmodium falciparum/fisiología , Receptor EphA2/genéticaAsunto(s)
Plaquetas , Malaria , Animales , Gránulos Citoplasmáticos , Modelos Animales de Enfermedad , RatonesRESUMEN
Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system.
