Evidence for Effects of Extracellular Vesicles on Physical, Inflammatory, Transcriptome and Reward Behaviour Status in Mice.

Nagiua Cuomo-Haymour,Irene Knuesel,Giorgio Bergamini,Felix Gantenbein,Ursina Nüesch,Christian Ineichen,Christopher Pryce,Hannes Sigrist,Giancarlo Russo,Luka Kulic

doi:10.3390/ijms23031028

Abstract

Immune-inflammatory activation impacts extracellular vesicles (EVs), including their miRNA cargo. There is evidence for changes in the EV miRNome in inflammation-associated neuropsychiatric disorders. This mouse study investigated: (1) effects of systemic lipopolysaccharide (LPS) and chronic social stress (CSS) on plasma EV miRNome; and (2) physiological, transcriptional, and behavioural effects of peripheral or central delivered LPS-activated EVs in recipient mice. LPS or CSS effects on the plasma EV miRNome were assessed by using microRNA sequencing. Recipient mice received plasma EVs isolated from LPS-treated or SAL-treated donor mice or vehicle only, either intravenously or into the nucleus accumbens (NAc), on three consecutive days. Bodyweight, spleen or NAc transcriptome and reward (sucrose) motivation were assessed. LPS and CSS increased the expression of 122 and decreased expression of 20 plasma EV miRNAs, respectively. Peripheral LPS-EVs reduced bodyweight, and both LPS-EVs and SAL-EVs increased spleen expression of immune-relevant genes. NAc-infused LPS-EVs increased the expression of 10 immune-inflammatory genes. Whereas motivation increased similarly across test days in all groups, the effect of test days was more pronounced in mice that received peripheral or central LPS-EVs compared with other groups. This study provides causal evidence that increased EV levels impact physiological and behavioural processes and are of potential relevance to neuropsychiatric disorders.

Highlights

Extracellular vesicles (EVs) are heterogeneous membrane-enclosed structures secreted by virtually all cell types, but most abundantly by immune cells [1], in the periphery and central nervous system (CNS) [2,3]
In order to explore these hypotheses, we conducted a first experiment with the aims to investigate and compare the effects of acute, systemic LPS and 15-day chronic social stress (CSS) on the plasma extracellular vesicles (EVs) miRNome (Experiment 1)
Li et al reported six of seven serum EV miRNAs that they measured were upregulated at 6 h after LPS, and four of these—miR-15a, miR-15b, miR146a, and miR-155—were upregulated in this study; each of these miRNAs is involved in inflammatory processes [43,44]

Summary

Introduction

Extracellular vesicles (EVs) are heterogeneous membrane-enclosed structures secreted by virtually all cell types, but most abundantly by immune cells [1], in the periphery and central nervous system (CNS) [2,3]. Various molecules are encapsulated into nascent EVs, including proteins, lipids, mRNAs, and high amounts of small non-coding RNAs, including microRNAs (miRNAs), thereby forming the EV “cargo” [3]. Loaded EVs can be transported in body fluids over short and long distances and their functionally active cargo can be transferred to recipient cells [5–8]. Evidence has been obtained for the integral involvement of EVs in the immune response including inflammation The latter is associated with changes in number [10], periphery-CNS passage [11], and cargo [12]

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