Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis.
OBJECTIVE
Cannabinoids are derivates of the marijuana component Δ(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 wild-type littermates (CB1(+/+) mice) were injected with bleomycin. CB1 signaling was activated in vivo with the selective agonist N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (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 inflammation-independent TSK-1 mouse model.


CONCLUSIONS
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 inflammation-driven models of fibrosis.
Marquart
Sieglinde
S
University of Erlangen-Nuremberg, Erlangen, Germany.
Zerr
Pawel
P
Akhmetshina
Alfiya
A
Palumbo
Katrin
K
Reich
Nicole
N
Tomcik
Michal
M
Horn
Angelika
A
Dees
Clara
C
Engel
Matthias
M
Zwerina
Jochen
J
Distler
Oliver
O
Schett
Georg
G
Distler
Jörg H W
JH
D000818:Animals; D016026:Bone Marrow Transplantation; D005355:Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018709:Statistics, Nonparametric
D043884:Receptor, Cannabinoid, CB1