Cannabinoid receptor 2 (CB2) is an immune cell localised GPCR that has been hypothesised 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 the murine dorsal air pouch model with WT and CB2 -/- 8-12 week old female and male C57BL\6 mice and found that acute neutrophil and Ly-6Chi monocyte recruitment in response to Zymosan was significantly enhanced in CB2 -/- mice. Additionally, levels of the metalloproteinase MMP-9 and the chemokines CCL2, CCL4 and CXCL10 in CB2 -/- pouch exudates were elevated at earlier time points. Importantly, using mixed bone marrow chimeras we revealed that the pro-inflammatory phenotype in CB2 -/- mice is neutrophil-intrinsic rather than stromal cell-dependent. Indeed, neutrophils isolated from CB2 null 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 the cannabinoid receptor CB2 plays a non-redundant role during acute neutrophil mobilisation 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.
Bibliographical noteCannabinoids to date have been shown to possess anti-inflammatory properties and the CB2 receptor is a promising therapeutic target for chronic inflammatory diseases and neuropathic pain. The majority of CB2 studies to date have focused on monocytes/macrophages and lymphocytes due to the high expression levels of the receptor in these cell types. However, CB2 function on neutrophils remains poorly defined. The key finding of our study is that global CB2 deletion enhances acute inflammation and, for the first time, conclusively demonstrates that this effect is neutrophil autonomous. By using mixed chimeric mice we can also exclude an endothelial cell or stromal cell mediated effect of CB2 on inflammatory cell recruitment, clarifying a point of contention within the current literature. Our work clearly demonstrates that, given their orchestrating role in inflammation initiation and progression, these short-lived immune cells could constitute a novel cell target for CB2 agonism in order to attenuate inflammatory diseases.
- Acute Inflammation
- Innate immunity
- leukocyte trafficking