Abstract
Severe psoriasis, a chronic inflammatory skin disease is increasingly being effectively managed by targeted immunotherapy but long-term immunotherapy poses health risk and loss of response. Therefore, there is a need for alternative therapy strategies. Mesenchymal stem/stromal cell (MSC) exosomes are widely known for their potent immunomodulatory properties. Here we investigated if topically applied MSC exosomes could alleviate psoriasis-associated inflammation. Topically applied fluorescent exosomes on human skin explants were confined primarily to the stratum corneum with <1% input fluorescence exiting the explant over a 24-h period. Nevertheless, topically applied MSC exosomes in a mouse model of imiquimod (IMQ) psoriasis significantly reduced IL-17 and terminal complement activation complex C5b-9 in the mouse skin. MSC exosomes were previously shown to inhibit complement activation, specifically C5b-9 complex formation through CD59. Infiltration of neutrophils into the stratum corneum is characteristic of psoriasis and neutrophils are a major cellular source of IL-17 in psoriasis through the release of neutrophil extracellular traps (NETs). We propose that topically applied MSC exosomes inhibit complement activation in the stratum corneum and this alleviates IL-17 release by NETS from neutrophils that accumulate in and beneath the stratum corneum.
Highlights
Psoriasis is a common chronic disease involving predominantly the skin and joints, and is associated with underlying genetic predispositions and inflammatory dysregulation [1]
Somes from the first day of IMQ induction, as is commonly practiced, was to allow assessexosomes from the first day of IMQ induction, as is commonly practiced, was to allow ment of the effect of Mesenchymal stem/stromal cell (MSC) exosomes on the psoriatic phenotype while minimizing any assessment of the effect of MSC exosomes on the psoriatic phenotype while minimizing any confounding effects on the induction of psoriasis by IMQ
We demonstrated that topically applied MSC exosomes can reduce the critical psoriatic cytokines, IL-17 and IL-23, and terminal complement complex, C5b-9
Summary
Psoriasis is a common chronic disease involving predominantly the skin and joints, and is associated with underlying genetic predispositions and inflammatory dysregulation [1]. Drugs used in systemic therapy for psoriasis include both small molecules such as methotrexate (MTX), retinoids, or cyclosporin, and more recently, biologics such as monoclonal antibodies and receptor fusion proteins. Most of the small molecules reduce cellular proliferation or suppress immune activity while the biologics target inflammatory cytokines in the IL-23/Th17 axis and TNF-α-signaling [4]. Long-term use of these systemic treatments is often complicated by toxic side effects such as hepatotoxicity, nephrotoxicity, hypertension, tremors, hypomagnesemia, hyperkalemia, and malignancies [5,6,7], inadequate long term patient compliance [8] and anti-drug responses [9,10]. There is still a need for alternative treatment modalities for at-risk or non-responsive patients
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