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Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment
Author(s) -
Kapellos Theodore S.,
Taylor Lewis,
Feuerborn Alexander,
Valaris Sophia,
Hussain Mohammed T.,
Rainger G. E.,
Greaves David R.,
Iqbal Asif J.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802524r
Subject(s) - inflammation , chemokine , cannabinoid receptor type 2 , immunology , receptor , proinflammatory cytokine , immune system , cannabinoid , cannabinoid receptor , biology , chemistry , agonist , medicine
Cannabinoid receptor (CB) 2 is an immune cell–localized GPCR that has been hypothesized to regulate the magnitude of inflammatory responses. However, there is currently no consensus as to the mechanism by which CB 2 mediates its anti‐inflammatory effects in vivo . To address this question, we employed a murine dorsal air pouch model with wild‐type and CB 2 −/− 8–12‐wk‐old female and male C57BL/6 mice and found that acute neutrophil and lymphocyte antigen 6 complex, locus C hi monocyte recruitment in response to Zymosan was significantly enhanced in CB 2 −/− mice. Additionally, levels of matrix metalloproteinase 9 and the chemokines C‐C motif chemokine ligand (CCL)2, CCL4, and C‐X‐C motif chemokine ligand 10 in CB 2 −/− pouch exudates were elevated at earlier time points. Importantly, using mixed bone marrow chimeras, we revealed that the proinflammatory phenotype in CB 2 −/− mice is neutrophil‐intrinsic rather than stromal cell–dependent. Indeed, neutrophils isolated from CB 2 −/− mice exhibited an enhanced migration‐related transcriptional profile and increased adhesive phenotype, and treatment of human neutrophils with a CB 2 agonist blocked their endothelial transmigration. Overall, we have demonstrated that CB 2 plays a nonredundant role during acute neutrophil mobilization to sites of inflammation and, as such, it could represent a therapeutic target for the development of novel anti‐inflammatory compounds to treat inflammatory human diseases.—Kapellos, T. S., Taylor, L., Feuerborn, A., Valaris, S., Hussain, M. T., Rainger, G. E., Greaves, D. R., Iqbal, A. J. Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment. FASEB J. 33, 6154–6167 (2019). www.fasebj.org