Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment

Theodore S Kapellos; Lewis Taylor; Alexander  Feuerborn; Sophia Valaris; Mohammed T Hussain; George Rainger; David R Greaves; Asif Jilani Iqbal

doi:10.1096/fj.201802524R

Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment

Theodore S Kapellos, Lewis Taylor, Alexander Feuerborn, Sophia Valaris, Mohammed T Hussain, George Rainger, David R Greaves, Asif Jilani Iqbal

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

171 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	6154-6167
Journal	FASEB Journal
Volume	33
Issue number	5
Early online date	29 Apr 2019
DOIs	https://doi.org/10.1096/fj.201802524R
Publication status	Published - 1 May 2019

Bibliographical note

Cannabinoids 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.

Keywords

Acute Inflammation
Cannabinoids
Innate immunity
leukocyte trafficking

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment",

abstract = "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. ",

keywords = "Acute Inflammation, Cannabinoids, Innate immunity, leukocyte trafficking",

author = "Kapellos, {Theodore S} and Lewis Taylor and Alexander Feuerborn and Sophia Valaris and Hussain, {Mohammed T} and George Rainger and Greaves, {David R} and Iqbal, {Asif Jilani}",

note = "Cannabinoids 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. ",

year = "2019",

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doi = "10.1096/fj.201802524R",

language = "English",

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pages = "6154--6167",

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AU - Kapellos, Theodore S

AU - Taylor, Lewis

AU - Feuerborn, Alexander

AU - Valaris, Sophia

AU - Hussain, Mohammed T

AU - Rainger, George

AU - Greaves, David R

AU - Iqbal, Asif Jilani

N1 - Cannabinoids 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.

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N2 - 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.

AB - 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.

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KW - Cannabinoids

KW - Innate immunity

KW - leukocyte trafficking

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DO - 10.1096/fj.201802524R

M3 - Article

SN - 0892-6638

VL - 33

SP - 6154

EP - 6167

JO - FASEB Journal

JF - FASEB Journal

IS - 5

ER -

Cannabinoid receptor 2 deficiency exacerbates inflammation and neutrophil recruitment

Abstract

Bibliographical note

Keywords

UN SDGs

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