Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment

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 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.

Activation of cannabinoid receptors promote periodontal cell adhesion and migration

“…First, cannabinoids induced migration and differentiation of stem cells, including mesenchymal stem cells (MSCs) and hemopoietic stem cells (HSCs), in various regenerative processes such as bone healing (Schmuhl, Ramer, Salamon, Peters, & Hinz, 2014). Second, they exhibited immunoregulatory effects by enhancing neutrophil migration and adhesion (Kapellos et al, 2019), modulating recruitment of microglial cells and chemotaxis of T lymphocytes (Ghosh, Preet, Groopman, & Ganju, 2006;Walter et al, 2003), and inducing natural killer cells against infectious viruses and tumour cells (Kishimoto et al, 2005) etc. Third, cannabinoids influenced tumour metastasis and treatment by reducing multiple myeloma cells viability and migration (Grimaldi et al, 2006;Nabissi et al, 2016), stimulated non-invasive phenotype in breast metastatic cells (Grimaldi et al, 2006), and inhibited lung cancer cell growth and metastasis (Preet, Ganju, & Groopman, 2007).…”

The Impact of Cannabinoid Receptor 2 Deficiency on Neutrophil Recruitment and Inflammation

“…In the same study the authors explored the effects of pharmacological modulation of CB2 signalling on human neutrophils. Human neutrophils treated with the CB2 agonist, JWH133, were shown to have reduced adhesion and transmigration across cytokine stimulated endothelial cell monolayers (Kapellos et al, 2019).…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…Cannabinoids via CB2Rs have been demonstrated to suppress T- and B-cell proliferation and function, and induce apoptosis of splenocytes and thymocytes [ 550 , 551 , 552 ]. Deficiency of CB2Rs has been demonstrated to cause an augmentation of inflammatory state and chemotactic functioning [ 553 ]. However, CB2R deficiency was also shown to reduce T- and B-cell population [ 554 ], and also resulted in an impaired B-cell retention and function [ 555 ].…”