Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis.
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.
Université Paris Descartes, Faculté de Médecine, Laboratoire d'immunologie, EA 1833, IFR Alfred Jost, 75679 Paris cedex 14, France.
Amélie
A
Servettaz
Niloufar
N
Kavian
Carole
C
Nicco
Vanessa
V
Deveaux
Christiane
C
Chéreau
Andrew
A
Wang
Andreas
A
Zimmer
Sophie
S
Lotersztajn
Bernard
B
Weill
Frédéric
F
Batteux
D000700:Analgesics / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000276:immunology*; D048588:Benzoxazines / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005355:Fibrosis; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D011897:Random Allocation; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000700:Analgesics; D001323:Autoantibodies; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D016877:Oxidants; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D006997:Hypochlorous Acid; D004264:DNA Topoisomerases, Type I