Neuropeptide Cortistatin Regulates Dermal and Pulmonary Fibrosis in an Experimental Model of Systemic Sclerosis

Introduction: Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy, and progressive fibrosis of the skin and internal organs. Because its aetiology is unknown, the identification of genes/factors involved in disease severity, differential clinical forms, and associated complications is critical for understanding its pathogenesis and designing novel treatments. Neuroendocrine mediators in the skin emerge as potential candidates. We investigated the role played by the neuropeptide cortistatin in a preclinical model of scleroderma. Methods: Dermal fibrosis was induced by repetitive intradermal injections of bleomycin in wild-type and cortistatin-deficient mice. The histopathological signs and expression of fibrotic markers were evaluated in the skin and lungs. Results: An inverse correlation between cortistatin levels and fibrogenic activation exists in the damaged skin and dermal fibroblasts. Bleomycin-challenged skin lesions of mice that are partially and totally deficient in cortistatin showed exacerbated histopathological signs of scleroderma, characterized by thicker and more fibrotic dermal layer, enlarged epidermis, and increased inflammatory infiltration in comparison to those of wild-type mice. Cortistatin deficiency enhanced dermal collagen deposits, connective tissue growth factor expression, loss of microvessels, and predisposition to suffer severe complications that co-occur with dermal exposition to bleomycin, including pulmonary fibrotic disease and increased mortality. Treatment with cortistatin mitigated these pathological processes. Discussion/Conclusion: We identify cortistatin as an endogenous break of skin inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis of scleroderma and associated complications. Cortistatin-based therapies emerge as attractive candidates to treat severe forms of systemic sclerosis and to manage fibrosis-related side effects of bleomycin chemotherapy in oncologic patients.