Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

NOD-like receptors are innate immunity sensors that provide an early and effective response to pathogenic or injury conditions. However, abnormalities in these receptors may cause excessive inflammation. Our studies have reported that an activation of the NLRP3-inflammasome complex in ethanol-treated astrocytes and in chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Considering the therapeutic role of the molecules contained in the extracellular vesicles (EVs) derived by mesenchymal stem cells (MSC-EVs), the present study aims to evaluate whether the intravenous administration of MSC-EVs from adipose tissue, through inhibiting the NLRP3 inflammasome activation, is capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrate that MSC-EVs ameliorate the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., NLRP1, NLRC4 and AIM2), as well as the alterations of inflammatory genes (IL-1β, IL-18, iNOS, NF-κB, MCP-1 and CX3CL1) and miRNAs (miR-21a-5p, miR-146a-5p and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide, for the first time, evidence of the therapeutic potential of MSC-derived EVs to restore the hippocampal neuroinflammatory response through the NLRP3 inflammasome activation induced by binge drinking in adolescence. ### Competing Interest Statement The authors have declared no competing interest. * CAMK2D : calcium/calmodulin dependent protein kinase II delta CCR5 : C-C chemokine receptor type 5 CD : Cluster of Differentiation CX3CL1 : C-X3-C motif chemokine ligand 1 or fractalkine CXCR4 : C-X-C motif chemokine receptor 4 DGCR8 : DiGeorge Critical Region 8 iNOS : inducible nitric oxide synthase IRAK : interleukin-1 receptor-associated kinase IRF4 : interferon regulatory factor 4 MAPK : mitogen-activated protein kinase MCP-1 : monocyte chemoattractant protein-1 NF-κB : nuclear factor-kappa B TGF-β : Transforming growth factor beta TIRAP : Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein.