Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis
| Autor: | Pawel Zerr, Matthias Engel, Jörg H W Distler, Sieglinde Marquart, Katrin Palumbo, Nicole Reich, Alfiya Akhmetshina, Georg Schett, Jochen Zwerina, Michal Tomcik, Angelika Horn, Clara Dees, Oliver Distler |
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| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Cannabinoid receptor medicine.medical_treatment Immunology Biology Statistics Nonparametric Mice Receptor Cannabinoid CB1 Rheumatology Fibrosis mental disorders medicine Cannabinoid receptor type 2 Animals Immunology and Allergy Pharmacology (medical) Bone Marrow Transplantation Inflammation Mice Knockout Scleroderma Systemic musculoskeletal neural and ocular physiology food and beverages medicine.disease Immunohistochemistry Transplantation medicine.anatomical_structure Neutrophil Infiltration nervous system Cancer research lipids (amino acids peptides and proteins) Bone marrow Cannabinoid Myofibroblast Infiltration (medical) |
| Zdroj: | Arthritis & Rheumatism. 62:3467-3476 |
| ISSN: | 0004-3591 |
| Popis: | Objective. Cannabinoids are derivates of the marijuana component 9 -tetrahydrocannabinol that exert their effects on mesenchymal cells and immune cells via CB1 and CB2 receptors. The aim of the present study was to evaluate the role of CB1 in systemic sclerosis. Methods. CB1-deficient (CB1 / ) mice and wildtype littermates (CB1 / mice) were injected with bleomycin. CB1 signaling was activated in vivo with the selective agonist N-(2-chloroethyl)-5Z,8Z,11Z,14Zeicosatetraenamide (ACEA). Bone marrow transplantation experiments were performed to investigate whether the phenotype of CB1 / mice was mediated by leukocytes or mesenchymal cells. The role of CB1 was also investigated in the TSK-1 mouse model. Results. CB1 / mice were protected from bleomycin-induced dermal fibrosis, with reduced dermal thickening, hydroxyproline content, and myofibroblast counts. Inactivation of CB1 decreased the number of infiltrating T cells and macrophages in lesional skin. In contrast, activation of CB1 with ACEA increased leukocyte infiltration and enhanced the fibrotic response to bleomycin. The phenotype of CB1 / mice was mimicked by transplantation of CB1 / mouse bone marrow into CB1 / mice, demonstrating that CB1 exerts its profibrotic effects indirectly by regulating leukocyte infiltration. Consistently, knockdown of CB1 did not prevent fibrosis in the inflammationindependent TSK-1 mouse model. Conclusion. We demonstrate that the cannabinoid receptor CB1 is crucial for leukocyte infiltration and secondary fibroblast activation and that inactivation of CB1 exerts potent antifibrotic effects in inflammationdriven models of fibrosis. |
| Databáze: | OpenAIRE |
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