The antifibrotic effect of α2AP neutralization in systemic sclerosis dermal fibroblasts and mouse models of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by the fibrosis of the skin and visceral organs, and peripheral circulatory disturbance. We recently demonstrated that α2-antiplasmin (α2AP), which is the physiological inhibitor of plasmin, is associated with the development of fibrosis. We observed that the administration of α2AP in mice induced fibrotic changes, such as increased dermal thickness, collagen production, and myofibroblast deposition. Conversely, α2AP neutralization prevented fibrotic changes in the bleomycin-induced mouse models of SSc. Interestingly, the α2AP neutralization also attenuated the production of autoantibodies in mouse models of SSc. Furthermore, we found that the expression of α2AP was elevated in dermal fibroblasts from patients with SSc. We also showed that α2AP treatment in the absence of plasmin induced extracellular matrix (ECM) production and myofibroblast formation in human normal dermal fibroblasts, and that α2AP neutralization reversed the pro-fibrotic phenotype of SSc dermal fibroblasts. Our findings demonstrated that α2AP has a pro-fibrotic effect probably not by the action as a plasmin inhibitor, and that the blocking of α2AP exerts an antifibrotic effect in humans and mice with SSc. This study may thus provide new insight into this process, which could eventually lead to the development of new clinical therapies for SSc.