Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL/6 mice that reproduces fibrosis, vasculopathy and autoimmunity

Walcy Rosolia Teodoro,Percival D Sampaio-Barros,Fernanda Degobbi T Q S Lopes,Margarete B G Vendramini,Lais Araujo Dos Santos,Vera Luiza Capelozzi,Esmeralda M Eher,Zelita Aparecida De Jesus Queiroz,Sergio Catanozi,Antonio Dos Santos Filho,Sandra De Morais Fernezlian,Cleonice Bueno,Sandra Gofinet Pasoto,Ana Paula Pereira Velosa

doi:10.1186/s13075-019-2052-2

Abstract

BackgroundType V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc). We characterized serological, functional, and histopathological features of the skin and lung in a novel SSc murine model induced by Col V immunization.MethodsFemale C57BL/6 mice (n = 19, IMU-COLV) were subcutaneously immunized with two doses of Col V (125 μg) emulsified in complete Freund adjuvant, followed by two intramuscular boosters. The control group (n = 19) did not receive Col V. After 120 days, we examined the respiratory mechanics, serum autoantibodies, and vascular manifestations of the mice. The skin and lung inflammatory processes and the collagen gene/protein expressions were analyzed.ResultsVascular manifestations were characterized by endothelial cell activity and apoptosis, as shown by the increased expression of VEGF, endothelin-1, and caspase-3 in endothelial cells. The IMU-COLV mice presented with increased tissue elastance and a nonspecific interstitial pneumonia (NSIP) histologic pattern in the lung, combined with the thickening of the small and medium intrapulmonary arteries, increased Col V fibers, and increased COL1A1, COL1A2, COL3A1, COL5A1, and COL5A2 gene expression. The skin of the IMU-COLV mice showed thickness, epidermal rectification, decreased papillary dermis, atrophied appendages, and increased collagen, COL5A1, and COL5A2 gene expression. Anti-collagen III and IV and ANA antibodies were detected in the sera of the IMU-COLV mice.ConclusionWe demonstrated that cutaneous, vascular, and pulmonary remodeling are mimicked in the Col V-induced SSc mouse model, which thus represents a suitable preclinical model to study the mechanisms and therapeutic approaches for SSc.

Highlights

Type V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc)
We found that increased mRNA expression of collagen V (Col V) gene and abnormal Col V deposition in pulmonary tissue and lung fibroblast were correlated with fibrosis and a worsened pulmonary function in SSc patients [22, 23]
Under the conditions of this study, we propose that C57BL/6 mice immunized with Col V can be considered a novel animal model that potentially contributes to the understanding of the links between inflammation, vascular injury, and fibrosis in SSc

Summary

Introduction

Type V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc). Functional, and histopathological features of the skin and lung in a novel SSc murine model induced by Col V immunization. Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disorder affecting the skin and the lung [1, 2]. Our first studies in animal models of SSc were performed in rabbits and showed vascular remodeling and fibrosis in the skin and lungs and immune reactivity after immunization with type V collagen (Col V) [12, 13]. The capacity of induction of pulmonary fibrosis in previous models using C57BL/6 mice was the main reason for the selection of these mice lineages

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