Our aim was to evaluate the roles of the
cannabinoid pathway in the induction and propagation of
systemic sclerosis (SSc) in a mouse model of diffuse SSc induced by
hypochlorite injections. BALB/c mice injected subcutaneously every day for 6 weeks with PBS or
hypochlorite were treated intraperitoneally with either WIN-55,212, an agonist of the
cannabinoid receptors 1 (CB1) and receptors 2 (CB2), with
JWH-133, a selective agonist of CB2, or with PBS. Skin and lung
fibrosis were then assessed by histological and biochemical methods, and the proliferation of fibroblasts purified from diseased skin was assessed by
thymidine incorporation.
Autoantibodies were detected by ELISA, and spleen cell populations were analyzed by flow cytometry. Experiments were also performed in mice deficient for CB2 receptors (Cnr2(-/-)).
Injections of
hypochlorite induced cutaneous and lung
fibrosis as well as increased the proliferation rate of fibroblasts isolated from fibrotic skin, splenic B cell counts, and levels of anti-
DNA topoisomerase-1
autoantibodies. Treatment with WIN-55,212 or with the selective CB2 agonist
JWH-133 prevented the development of skin and lung
fibrosis as well as reduced fibroblast proliferation and the development of
autoantibodies. Experiments performed in CB2-deficient mice confirmed the influence of CB2 in the development of systemic
fibrosis and autoimmunity. Therefore, we demonstrate that the
CB2 receptor is a potential target for the treatment of SSc because it controls both skin fibroblast proliferation and the autoimmune reaction.