Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

• Published in: Blood Vol. 120; no. 18; pp. 3741 - 3749
• Main Authors: Adhikary, Sabina, Kocieda, Virginia P., Yen, Jui-Hung, Tuma, Ronald F., Ganea, Doina
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Cell Movement; Chemotaxis, Leukocyte - immunology; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Hematologic and hematopoietic diseases; Immunobiology; Matrix Metalloproteinase 9 - immunology; Matrix Metalloproteinase 9 - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB2 - immunology; Receptor, Cannabinoid, CB2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology; Dendritic cell; Hematology; Enzyme; Rodentia; Metalloendopeptidases; CB2 cannabinoid receptor; Gelatinase B; Peptidases; Cell motility; Signal transduction; Vertebrata; Mammalia; Mouse; Antigen presenting cell; Animal; Hydrolases; Cell migration
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-06-435362

Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9–dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs.