The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing

Abstract

Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase-1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble -ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor-α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor κB pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…Production of IL‐1Ra in MSCs is regulated by the local concentration of inflammatory cytokines (particularly TNF‐α and IL‐1β) and Fas:Fas‐associated phosphatase‐1 (Fap‐1):Caveolin‐1 (Cav‐1) complex. When MSCs engraft in the inflammatory microenvironment of the nonhealing wounds, high levels of TNF‐α and IL‐1β induce simultaneous upregulation of membrane‐bound Fas and Fap‐1 and enhanced production of immunosuppressive cytokines, including IL‐1Ra . Fas and Fap‐1 interact with Cav‐1 and form a Fas:Fap‐1:Cav‐1 complex which activates a common soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE)‐mediated membrane fusion mechanism resulting in the release of sEVs.…”

“…Fas and Fap‐1 interact with Cav‐1 and form a Fas:Fap‐1:Cav‐1 complex which activates a common soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE)‐mediated membrane fusion mechanism resulting in the release of sEVs. MSC‐derived IL‐1Ra, associated with released sEVs, diffuses through the injured skin and in paracrine and endocrine manner, attenuates IL‐1β‐driven inflammation, enabling enhanced wound healing (Figure ) …”

“…As recently revealed by Kou and colleagues, MSC‐derived IL‐1Ra is secreted in the extracellular space associated with small extracellular vesicles (sEVs) . Production of IL‐1Ra in MSCs is regulated by the local concentration of inflammatory cytokines (particularly TNF‐α and IL‐1β) and Fas:Fas‐associated phosphatase‐1 (Fap‐1):Caveolin‐1 (Cav‐1) complex.…”

“…26 As recently revealed by Kou and colleagues, MSCderived IL-1Ra is secreted in the extracellular space associated with small extracellular vesicles (sEVs). 30 Production of IL-1Ra in MSCs is regulated by the local concentration of inflammatory cytokines (particularly TNF-α and IL-1β) and Fas:Fas-associated phosphatase-1 (Fap-1):Caveolin-1 (Cav-1) complex. When MSCs engraft in the inflammatory microenvironment of the nonhealing wounds, high levels of TNF-α and IL-1β induce simultaneous upregulation of membrane-bound Fas and Fap-1 and enhanced production of immunosuppressive cytokines, including IL-1Ra.…”

“…When MSCs engraft in the inflammatory microenvironment of the nonhealing wounds, high levels of TNF-α and IL-1β induce simultaneous upregulation of membrane-bound Fas and Fap-1 and enhanced production of immunosuppressive cytokines, including IL-1Ra. 30 Fas and Fap-1 interact with Cav-1 and form a Fas:Fap-1:Cav-1 complex which activates a common soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion mechanism resulting in the release of sEVs. MSC-derived IL-1Ra, associated with released sEVs, diffuses through the injured skin and in paracrine and endocrine manner, attenuates IL-1β-driven inflammation, enabling enhanced wound healing (Figure 1).…”