Abstract
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 CB2 mediates its anti-inflammatory effects in vivo. To address this question, we employed a murine dorsal air pouch model with wild-type and CB2−/− 8–12-wk-old female and male C57BL/6 mice and found that acute neutrophil and lymphocyte antigen 6 complex, locus Chi monocyte recruitment in response to Zymosan was significantly enhanced in CB2−/− 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 CB2−/− pouch exudates were elevated at earlier time points. Importantly, using mixed bone marrow chimeras, we revealed that the proinflammatory phenotype in CB2−/− mice is neutrophil-intrinsic rather than stromal cell–dependent. Indeed, neutrophils isolated from CB2−/− mice exhibited an enhanced migration-related transcriptional profile and increased adhesive phenotype, and treatment of human neutrophils with a CB2 agonist blocked their endothelial transmigration. Overall, we have demonstrated that CB2 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.
Highlights
Since the discovery of cannabinoid receptor (CB) 1, CB2, and their endogenous lipid ligands, almost 3 decades of work has established that these 2 GPCRs and their cognate ligands, alongside the enzymes that synthesize and degrade these endogenous lipids, make up the endocannabinoid system [1,2,3,4]
We began by analyzing the immune cell composition of dorsal air pouches from WT and CB22/2 female mice under baseline conditions and upon challenge with Zymosan (100 mg) across a range of time points
We found that neutrophils [CD45+, CD1152, lymphocyte antigen 6 complex (Ly-6G)+, and low Ly-6C (Ly-6Clo); Supplemental Fig. S1C, G] as well as the Ly-6Clo and high Ly-6C (Ly-6Chi) monocyte (CD45+, CD115+; Supplemental Fig. S1D, H) populations were present in the pouches of both WT and CB22/2 animals, and their numbers were comparable between the 2 genotypes (Supplemental Fig. S1I–L)
Summary
Since the discovery of cannabinoid receptor (CB) 1, CB2, and their endogenous lipid ligands (known as the endocannabinoids), almost 3 decades of work has established that these 2 GPCRs and their cognate ligands, alongside the enzymes that synthesize and degrade these endogenous lipids, make up the endocannabinoid system [1,2,3,4] Both CB1 and CB2 are class A rhodopsin-like GPCRs and are Gi/o-coupled; their ligation results in the inhibition of adenylyl cyclase and the lowering of intracellular cAMP levels [5]. One hypothesis put forward is that activation of CB2 blocks immune cell chemotaxis; we recently found that CB2 does not play a role in regulating primary macrophage chemotaxis [26]. Most previous studies investigating CB2 within inflammation have used indirect or semiquantitative measures of immune cell recruitment and only examine a single time point
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