This study investigated a novel mechanism of peripheral contribution to neuroinflammation mediated by circulating exosomes. Initially the microglial and astrocytic activation in the brain was demonstrated by using the peripheral LPS induced neuroinflammation model which is consistent with many other reports [28]. Next, the role of serum-derived exosomes was investigated to know if they can cause neuroinflammation during acute systemic inflammation induced by a single intraperitoneal LPS injection.
The finding of increased exosome protein concentration as determined by intact as well as lysed protein quantification of exosomal fractions after LPS injection suggests that there is an increase in the number of secreted exosomes and also points towards the alteration in the exosomal content and cargo during systemic inflammatory conditions, indicating a possible role of exosomes in mediating intercellular communication during inflammatory conditions.
Exosomes derived from the sera of mice challenged with LPS caused significant upregulation of proinflammatory genes Il1b, Tnf, Il6 and 1l1a in cultured BV2, C8-D1A and Bend.3 cells, demonstrating the inflammatory potential of the exosomes during systemic inflammation. More interestingly, the supernatant obtained after the precipitation of exosomes was not able to induce such effect, suggesting that the exosomes mediate such functional effects in the recipient cells during inflammatory conditions and communicate with the distant cells. Furthermore, these exosomes when injected via tail vein led to an increase in the proinflammatory cytokine genes Tnf, Il1b, chemokine genes Ccl2, Ccl5, and pan reactive gene Lcn2. This suggests that the exosomes might be able to carry proinflammatory cargo from the periphery into the CNS and further induce neuroinflammation. However, this could also be due to the peripheral immune responses to the injected exosomes, which can also further cause neuroinflammation. Additionally, the exosomes derived from the sera of the mice injected with LPS but not PBS had elevated levels of proinflammatory cytokines IL-6, KC/GRO, TNF-α, IL-12p70, IFN-γ, IL-1β, IL-2, IL-4, IL-5 and IL-10.
Taken together these results suggest that peripheral circulating exosomes during systemic inflammatory conditions can undergo alteration in their content and are further capable of reaching the CNS to induce the upregulation of proinflammatory cytokines, and also activate microglia, astrocytes and cerebral endothelial cells and finally cause neuroinflammation. These observations suggest that exosomes may serve as an additional way in mediating the activation of neuroinflammatory processes during systemic inflammatory conditions and help to understand the mechanism of communication between the brain’s immune system and the peripheral immune system.
However, it is important to know the role of choroid-plexus epithelium (CP) and blood brain barrier endothelium in mediating the transport of SDEL from the periphery and the CNS. Recently it is shown that epithelial cells of the CP sense and relay the peripheral inflammatory status to the CNS by releasing the extracellular vesicles into the CSF, which transfer this pro-inflammatory message to recipient brain cells [29]. Nevertheless, it is still unclear if the peripheral inflammatory exosomes have any preference in mediating this effect on the CP epithelial cells compared to BBB endothelial cells, and if the exosomes released by the peripheral immune cells travel into the CNS via the CP and/or BBB.
Further studies are required to primarily understand the precise mechanism by which exosome mediated neuroinflammation occurs, to know which cells in the CNS are the recipients of peripheral exosomes during systemic inflammatory conditions. It is also worthwhile to know if exosomal biogenesis associated with miRNA packaging by the peripheral immune effector cells contributes to the neuroinflammatory signaling cascade in the CNS.