The Regulation of Skin Fibrosis in Systemic Sclerosis by Extracellular ATP via P2Y2 Purinergic Receptor

Abstract

Tissue injury/hypoxia and oxidative stress induced-extracellular adenosine triphosphate (ATP) can act as damage-associated molecular pattern molecules, which initiate inflammatory response. Our objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release and that extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptor expression levels between normal and SSc fibroblasts. Nonselective P2 receptor antagonist and selective P2Y 2 receptor antagonists, kaempferol and AR-C118925XX, significantly inhibited ATP-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. ATP-induced IL-6 production was significantly inhibited by p38 inhibitors, SB203580, and doramapimod. Collagen type I production in SSc fibroblasts by ATP-induced IL-6/IL-6 receptor trans-signaling was inhibited by kaempferol and SB203580. The amount of ATP in bleomycin-treated skin was increased, and administration of AR-C118925XX significantly inhibited bleomycin-induced dermal fibrosis in mice. These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc and that extracellular ATP-induced phosphorylation of p38 via P2Y 2 receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y 2 receptor antagonist therapy could be a treatment for skin sclerosis in patients with SSc.

Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation

“…Also, it was already described that Staphylococcus aureus USA300, one of the most prevalent bacterial species identified in chronic wounds, exploits the immunomodulatory characteristics of ADO to subvert host immune response (50), retarding the healing of infected wounds. Lastly, ADO and ATP also promote fibrosis when released in high concentrations or chronically (51)(52)(53), which denotes a negative aspect in the case of topically application.…”

Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress

“…P2X receptors are ATP-gated ion channels, and P2Y receptor is a G protein-coupled receptor [47]. We recently identified that hypoxia enhanced ATP release, and extracellular ATP-induced phosphorylation of p38 via P2Y 2 receptor enhanced IL-6 and collagen type I production in SSc fibroblasts [50]. Our previous findings suggested that kaempferol also might inhibit extracellular ATP-induced IL-6/collagen type I production in vivo by the inhibition of ATP:P2Y 2 receptor signaling.…”

Zinc deficiency exacerbates pressure ulcers by increasing oxidative stress and ATP in the skin

“…The amount of ATP in the mouse skin was measured using "Tissue" ATP assay kit (TOYO INK) according to the manufacturer`s protocol and the previously described protocols [20].…”

“…There is recent evidence suggesting that extracellular ATP can serve as a damage-associated molecular patterns (DAMPs) molecule that initiates an inflammatory response through autocrine/paracrine signaling [18]. ATP can be released from cells by various stimulators, including mechanical stress, tissue injury, inflammation, and hypoxia [19,20]. Further, in PUs, it is assumed that ATP is released extracellularly by physical and hypoxic stimulation due to skin pressure.…”