Circulating exosomes may act as a neuroinflammatory mediator in systemic inflammation

Neuroinflammation is implicated in the development and progression of many neurodegenerative diseases. Conditions that lead to a peripheral immune response are often associated with inflammation in the central nervous system (CNS), suggesting a communication between the peripheral immune system and the neuroimmune system. The underlying mechanism of this relationship remains largely unknown; however, experimental studies have demonstrated that exposure to infectious stimuli, such as lipopolysaccharide (LPS) or high-fat diet (HFD) feeding, result in profound peripheral- and neuro-inflammation.

Using the model of endotoxemia with LPS, researchers from the University of Tennessee Health Science Center studied the role of serum-derived exosomes in mediating neuroinflammation. They purified circulating exosomes from the sera of LPS-challenged mice, which were then intravenously injected into normal adult mice.

The researchers found that the recipient mice that received serum-derived exosomes from LPS-challenged mice exhibited elevated microglial activation. Moreover, they observed astrogliosis, increased systemic pro-inflammatory cytokine production, and elevated CNS expression of pro-inflammatory cytokine mRNA and the inflammation-associated microRNA (miR-155) in these recipient mice. Gene expression analysis confirmed that many inflammatory microRNAs were significantly upregulated in the purified exosomes under LPS-challenged conditions. Th e researchers observed accumulated signaling within the microglia of mice that received tail-vein injections of fluorescently labeled exosomes though the percentage of those microglial cells was found low. Finally, purified LPS-stimulated exosomes from blood when infused directly into the cerebral ventricles provoked significant microgliosis and, to a lesser extent, astrogliosis.

Exosomes isolated from LPS-treated mice increase CD68-positive cells

a Photomicrographs of the hippocampal (Hp), neocortical (Cx), and lateral ventricular (LV) areas from C57BL/6J mice. Mice were intravenously injected 1 mg of exosomes (in 200 μl PBS) isolated from the sera of donor mice 6 h after intraperitoneal injection of PBS or 10 mg/kg LPS. The recipient mice were euthanized after 24 h. Brain sections were stained with anti-CD68 antibody (green) and DAPI (blue). Scale bar, 50 μm. b Higher magnification images of the white-dotted box area from a. Figures are presented in the following sequence: upper left, CD68 (green); upper right, Iba1 (red); lower left, merge of CD68 and Iba1; and lower right, DAPI (blue). Co-localization of CD68 and Iba1 (white arrowheads). DG dentate gyrus. Scale bar, 20 μm. c Quantification of CD68-positive cells in the hippocampal, neocortical, and lateral ventricular areas. n = 3–5 per group. Data represent mean ± SEM; *P < 0.05