The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis.

OBJECTIVE The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis. METHODS Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed. RESULTS CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis. CONCLUSION Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.

[1]  A. Akhmetshina,et al.  Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis. , 2009, Rheumatology.

[2]  Oliver Distler,et al.  Dual inhibition of c‐abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  N. Davoust,et al.  The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis. , 2008, The Journal of biological chemistry.

[4]  J. Zwerina,et al.  Src kinases in systemic sclerosis: central roles in fibroblast activation and in skin fibrosis. , 2008, Arthritis and rheumatism.

[5]  K. Mackie,et al.  Cannabinoid Receptors: Where They are and What They do , 2008, Journal of neuroendocrinology.

[6]  H. Friess,et al.  Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells , 2008, PloS one.

[7]  S. Werner,et al.  Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System , 2007, Science.

[8]  David Abraham,et al.  Systemic sclerosis: a prototypic multisystem fibrotic disorder. , 2007, The Journal of clinical investigation.

[9]  E. Williamson,et al.  Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. , 2007, Journal of dermatological science.

[10]  M. Malumbres,et al.  Cannabinoid receptors as novel targets for the treatment of melanoma , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  D. Abraham,et al.  Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. , 2005, Arthritis and rheumatism.

[12]  T. Klein Cannabinoid-based drugs as anti-inflammatory therapeutics , 2005, Nature Reviews Immunology.

[13]  Liying Li,et al.  Antifibrogenic role of the cannabinoid receptor CB2 in the liver. , 2005, Gastroenterology.

[14]  T. Bonner,et al.  Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. , 2000, European journal of pharmacology.

[15]  S. Munro,et al.  Molecular characterization of a peripheral receptor for cannabinoids , 1993, Nature.

[16]  T. Bonner,et al.  Structure of a cannabinoid receptor and functional expression of the cloned cDNA , 1990, Nature.

[17]  E. Vuorio,et al.  Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. , 1988, The Journal of investigative dermatology.

[18]  Oliver Distler,et al.  Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. , 2009, Arthritis and rheumatism.

[19]  U. Müller-Ladner,et al.  Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. , 2006, Arthritis and rheumatism.