Abstract
The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non-activated monocytes. These exosomes alone can activate human brain microvascular endothelial cells to stimulate adhesion molecules, CCL2, ICAM1, VCAM1 and cytokines, IL1β and IL6. This activation is through the toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) pathway that activates nuclear factor-κB and increases monocyte chemotaxis. Inhibition of monocyte exosome release reverses endothelial cell activation and monocyte chemotaxis. Our study suggests that activated monocytes have an impact on brain vascular function through intercellular exosome signaling.
Highlights
Exosomes have emerged as a new class of bio-nanoparticles that have been recognized to potentially change the face of physiological and pathological conditions in humans
We first wanted to determine that Human brain microvascular endothelial cells (HBMECs) take up exosomes from calcein AM stained monocytes on top of a dual chamber system
The HBMECs cocultured with monocytes that were incubated with exosome inhibitor, GW4869 (EXOi) showed no green fluorescence (Fig. 1A, right panel)
Summary
Exosomes have emerged as a new class of bio-nanoparticles that have been recognized to potentially change the face of physiological and pathological conditions in humans. We recently predicted an inflammatory disease mechanism in which human umbilical vein endothelial cells (HUVECs) actively expressed chemokine (C-C motif) ligand 2 (CCL2), interleukin 6 (IL6) and intercellular adhesion molecule 1 (ICAM1) genes after exposure to exosomes derived from interferon alpha (IFNα), lipopolysaccharide (LPS) or IFNα followed by LPS (I/L) stimulated monocytes[2]. This occurs via the activation of the toll like receptor 4 (TLR4)/Myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. The recipient cells show increased expression of these miRNAs triggering immune dysfunction related proinflammatory pathways[10]
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