Cannabinoid receptor 2 activation reduces intestinal leukocyte recruitment and systemic inflammatory mediator release in acute experimental sepsis

Lehmann, Christian; Kianian, Mandana; Zhou, Juan; Küster, Inga; Kuschnereit, Rieke; Whynot, Sara; Hung, Orlando; Shukla, Romesh; Johnston, Brent; Černý, V.; Pavlović, Dragan; Spassov, Alexander; Kelly, Melanie E. M.

doi:10.1186/cc11248

Cited by 50 publications

(41 citation statements)

References 28 publications

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“…Previous studies showed that the CB2R appears to produce both immunoenhancing and immunosuppressing effects during sepsis depending upon the cell type examined and severity of injury inflicted [14–17]. Our studies presented here showed that CB2R activation produced immunosuppressing effects no matter in LPS-triggered macrophages or ConA-triggered splenocytes, which is consistent with a previous report that the inhibition of LPS mediated NO release by WIN55212 was mediated by CBR2 in murine macrophages [35].…”

Section: Discussionsupporting

confidence: 92%

“…While in another study, CB2R seems like a strong destroyer in the same sepsis model [15]. Cannabinoid antagonist AM 281 was reported to reduce mortality rate after CLP in rats [16], while very recently, Lehmann and his colleagues found that CB2R activation reduced intestinal leukocyte recruitment and inflammation in rat acute sepsis models [17]. These controversial results leave this issue ambiguous.…”

Section: Introductionmentioning

confidence: 99%

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Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

Gui

Sun

Luo

et al. 2013

Mediators of Inflammation

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The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R−/−). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R−/− splenocytes but completely abolished in CB2R−/− peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks IκBα degradation and NF-κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

Gui

Sun

Luo

et al. 2013

Mediators of Inflammation

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“…However, activation of the CB 2 R by its agonist HU308 reduced plasma levels of pro-inflammatory cytokines in endotoxemic rats (Lehmann et al, 2012). Administration of the EC, anandamide, decreased the levels of the proinflammatory cytokines IL-12 and IL-23 in vitro in activated microglial cells (Correa et al, 2009).…”

Section: Ecs In Sepsismentioning

confidence: 99%

CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

et al. 2016

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The endocannabinoid system (ECS) is involved in many physiological processes and has been suggested to play a critical role in the immune response and the central nervous system (CNS). Therefore, ECS modulation has potential therapeutic effects on immune dysfunctional disorders, such as sepsis and CNS injury-induced immunodeficiency syndrome (CIDS). In sepsis, excessive release of pro- and anti-inflammatory mediators results in multi-organ dysfunction, failure, and death. In CIDS, an acute CNS injury dysregulates a normally well-balanced interplay between CNS and the immune system, leading to increased patients’ susceptibility to infections. In this review, we will discuss potential therapeutic modulation of the immune response in sepsis and CNS injury by manipulation of the ECS representing a novel target for immunotherapy.

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“…In vitro studies suppose that the agonist activity of BCP in relation to CB2 receptors is the main mechanism responsible for inhibiting the proinflammatory pathways and consequently the synthesis of cytokines such as IL‐1 β , IL‐6, IL‐8 and TNF– α . CB2 agonists have been shown to decrease leukocyte adhesion and plasma levels of inflammatory mediators, such as TNF‐ α and IL‐1 β , in models of experimental sepsis . Similarly, the literature also reports DHA inhibitory activity on TNF‐ α , IL‐1 β and IFN‐ γ , as well as potent inhibition of PMN migration, through increased activation of PPAR‐ γ and reduced activation of NF‐ K B .…”

Section: Discussionmentioning

confidence: 98%

Anti‐inflammatory activity of β‐caryophyllene combined with docosahexaenoic acid in a model of sepsis induced by Staphylococcus aureus in mice

et al. 2019

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BACKGROUND Sepsis is a set of serious organic manifestations caused by an infection, whose progression culminates in exacerbated inflammation and oxidative stress, poor prognosis, and high hospital costs. Antioxidants used against sepsis have been evaluated, including essential oils such as β‐caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The aim of this study was to evaluate the anti‐inflammatory activity of the association of these two compounds. RESULTS Treatment with BCP‐DHA, at a dose of 200 μL/animal, significantly inhibited the migration of neutrophils in a Cg‐induced peritonitis model. After Staphylococcus aureus infection, in the groups treated with BCP‐DHA there was a significant decrease in the total and differential count of leukocytes, increased expression of cytokines TNF‐α and IFN‐γ in treated groups, an increase of IL‐4 and IL‐5 in B/D and B/D + SA groups, and an augmentation of IL‐6 and IL‐12 groups in B/D + SA groups. Histological and bacterial analysis revealed lower neutrophil migration and lower bacterial load in the infected and treated groups. CONCLUSION In general, the BCP‐DHA association presented anti‐inflammatory activity against two different models of acute inflammation and infection, showing promising potential as a therapeutic adjuvant in sepsis. © 2019 Society of Chemical Industry

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Cannabinoid receptor 2 activation reduces intestinal leukocyte recruitment and systemic inflammatory mediator release in acute experimental sepsis

Cited by 50 publications

References 28 publications

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice

CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

Anti‐inflammatory activity of β‐caryophyllene combined with docosahexaenoic acid in a model of sepsis induced by Staphylococcus aureus in mice

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