CB2 Cannabinoid Receptors Contribute to Bacterial Invasion and Mortality in Polymicrobial Sepsis

Johns Hopkins School of Medicine, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(7):e6409. DOI: 10.1371/journal.pone.0006409
Source: PubMed


Sepsis is a major healthcare problem and current estimates suggest that the incidence of sepsis is approximately 750,000 annually. Sepsis is caused by an inability of the immune system to eliminate invading pathogens. It was recently proposed that endogenous mediators produced during sepsis can contribute to the immune dysfunction that is observed in sepsis. Endocannabinoids that are produced excessively in sepsis are potential factors leading to immune dysfunction, because they suppress immune cell function by binding to G-protein-coupled CB(2) receptors on immune cells. Here we examined the role of CB(2) receptors in regulating the host's response to sepsis.
The role of CB(2) receptors was studied by subjecting CB(2) receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB(2) receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB(2) receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-kappaB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB(2) receptor deficiency prevents apoptosis in lymphoid organs and augments the number of CD11b(+) and CD19(+) cells during CLP.
Taken together, our results establish for the first time that CB(2) receptors are important contributors to septic immune dysfunction and mortality, indicating that CB(2) receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.

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    • "The best known representative of this group is the endocannabinoid anandamide (N-arachidonoylethanolamine anandamide, AEA) (Alexander and Kendall, 2007; Correa et al., 2009; Pertwee et al., 2010). The cannabinoid (CB) 2 receptor (Alexander et al., 2013a) has been linked to the anti-inflammatory effects of anandamide and other endocannabinoids and is predominantly expressed by cells of the immune system (Bátkai et al., 2007; Csóka et al., 2009; Mukhopadhyay et al., 2010; Basu and Dittel, 2011). At the same time it is clear that not all NAEs exclusively bind to CB1 or CB2 receptors, but often also (or instead) show affinity for GPR55, GPR18, GPR119, transient receptor potential channel vanilloid subtype 1 (TRPV1; see Alexander et al., 2013b) or PPARs (Alexander and Kendall, 2007; Di Marzo et al., 2007; Pertwee et al., 2010; Maccarrone, 2013; for nomenclature see Alexander et al., 2013c). "
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    ABSTRACT: DHEA (N-docosahexaenoylethanolamine) is the ethanolamine conjugate of the long chain polyunsaturated n-3 fatty acid DHA (docosahexaenoic; 22 : 6n-3). Its concentration in animal tissues and human plasma increases when diets rich in fish or krill oil are consumed. DHEA displays anti-inflammatory properties in vitro and was found to be released during an inflammatory response in mice. Here we further examine possible targets involved in the immune-modulating effects of DHEA. Antagonists for CB1 , CB2 and PPAR were used to explore effects of DHEA on NO release by LPS-stimulated RAW264.7 cells. Possible involvement of CB2 receptors was also studied by comparing effects in LPS-stimulated peritoneal macrophages obtained from CB2 (-/-) and CB(+/+) mice. Effects on NF-κB activation were determined using a reporter cell line. To study DHEA effects on COX-2 and LOX activity, 21 different eicosanoids produced by LPS-stimulated RAW264.7 cells were quantified by LC-MS/MS. Finally, effects on mRNA expression profiles were analysed using gene arrays followed by Ingenuity(®) Pathways Analysis. Effects of DHEA on NO release appeared to be independent from CB1 , CB2 or PPAR receptors. NF-κB and IFNβ, key elements of the MyD88-dependent and MyD88-independent pathways were not decreased. By contrast, DHEA significantly reduced levels of several COX-2 generated eicosanoids. Gene expression analysis provided support for an effect on COX-2-mediated pathways. Our findings suggest that anti-inflammatory effects of DHEA in macrophages are predominantly taking place via inhibition of eicosanoids produced through COX-2.
    Full-text · Article · Apr 2014 · British Journal of Pharmacology
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    • "The aim of our study was to investigate the effects of CB2R manipulation (activation or inhibition) in two different acute experimental sepsis models, given the conflicting studies of Tschöp and colleagues [9] and Csoka and colleagues [10]. We used 2 experimental sepsis models: endotoxemia and colon ascendens stent peritonitis (CASP)-induced sepsis. "
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    ABSTRACT: Introduction Cannabinoid receptor 2 (CB2R) expression is upregulated during sepsis. However, there are conflicting results regarding the effects of CB2R modulation in the hyperinflammatory phase of the disease. The aim of this study was therefore to investigate the effects of CB2R manipulation on leukocyte activation within the intestinal microcirculation in two acute experimental sepsis models. Methods In the endotoxemia model we studied four groups of Lewis rats: controls, lipopolysaccharide (LPS), LPS + CB2R agonist HU308 (2.5 mg/kg), and LPS + CB2R antagonist AM630 (2.5 mg/kg). In the colon ascendens stent peritonitis (CASP)-induced sepsis model we also studied four groups: sham group, CASP and CASP + CB2R agonist (HU308, 2.5 or 10 mg/kg). Intravital microscopy was performed 2 hours following LPS/placebo administration or 16 hours following CASP/sham surgery to quantify intestinal leukocyte recruitment. Additionally, hemodynamic monitoring, histological examinations and measurements of inflammatory mediators were performed. Results HU308 administration significantly reduced intestinal leukocyte adhesion in both acute sepsis models. The systemic levels of inflammatory mediators were significantly reduced by 10 mg/kg HU308 treatment in CASP animals. Conclusion CB2R activation reduces leukocyte activation and systemic release of inflammatory mediators in acute experimental sepsis. Drugs targeting the CB2R pathway may have therapeutic potential in sepsis.
    Full-text · Article · Mar 2012 · Critical care (London, England)
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