Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis

Giacomo Casella, F Colombo, A Finardi, H Descamps, G Ill-Raga, A Spinelli, P Podini, M Bastoni, G Martino, L Muzio, R Furlan

Research output: Contribution to journalArticle

Abstract

Extracellular vesicles (EVs) play a major role in cell-to-cell communication in physiological and pathological conditions, and their manipulation may represent a promising therapeutic strategy. Microglia, the parenchymal mononuclear phagocytes of the brain, modulate neighboring cells also through the release of EVs. The production of custom EVs filled with desired molecules, possibly targeted to make their uptake cell specific, and their administration in biological fluids may represent a valid approach for drug delivery. We engineered a murine microglia cell line, BV-2, to release EVs overexpressing the endogenous “eat me” signal Lactadherin (Mfg-e8) on the surface to target phagocytes and containing the anti-inflammatory cytokine IL-4. A single injection of 107IL-4+Mfg-e8+EVs into the cisterna magna modulated established neuroinflammation and significantly reduced clinical signs in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Injected IL-4+Mfg-e8+EVs target mainly phagocytes (i.e., macrophages and microglia) surrounding liquoral spaces, and their cargo promote the upregulation of anti-inflammatory markers chitinase 3-like 3 (ym1) and arginase-1 (arg1), significantly reducing tissue damage. Engineered EVs may represent a biological drug delivery tool able to deliver multiple functional molecules simultaneously to treat neuroinflammatory diseases. Extracellular vesicles (EVs) are a physiological way of intercellular communication. We show here that it is possible to deliver EVs engineered to contain different molecules for therapeutic purposes. Using this strategy, we have successfully delivered an anti-inflammatory cytokine to treat a mouse model of multiple sclerosis. © 2018 The American Society of Gene and Cell Therapy
Original languageEnglish
Pages (from-to)2107-2118
Number of pages12
JournalMolecular Therapy
Volume26
Issue number9
DOIs
Publication statusPublished - 2018

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Interleukin-4
Multiple Sclerosis
Microglia
Phagocytes
Anti-Inflammatory Agents
Cytokines
Cisterna Magna
Extracellular Vesicles
Arginase
Chitinases
Autoimmune Experimental Encephalomyelitis
Cell- and Tissue-Based Therapy
Cell Communication
Pharmaceutical Preparations
Genetic Therapy
Up-Regulation
Macrophages
Cell Line
Injections
Brain

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Extracellular Vesicles Containing IL-4 Modulate Neuroinflammation in a Mouse Model of Multiple Sclerosis. / Casella, Giacomo; Colombo, F; Finardi, A; Descamps, H; Ill-Raga, G; Spinelli, A; Podini, P; Bastoni, M; Martino, G; Muzio, L; Furlan, R.

In: Molecular Therapy, Vol. 26, No. 9, 2018, p. 2107-2118.

Research output: Contribution to journalArticle

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