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CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis.

Csóka B, Németh ZH, Mukhopadhyay P, Spolarics Z, Rajesh M, Federici S, Deitch EA, Bátkai S, Pacher P, Haskó G - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT

Background: 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.

Methods and findings: 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.

Conclusions: 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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Related in: MedlinePlus

Effect of CB2 receptor inactivation on the leukocyte cell subsets in the blood during CLP.Numbers of total white cell (a), as well as CD11b+ (b), CD19+ (c), and CD3+ (d) cells were monitored in blood by flow cytometric analysis after 16 hours of sepsis induced by CLP. Data are the mean±SEM of n = 6–9 mice per group. *p<0.05; **p<0.01.
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pone-0006409-g006: Effect of CB2 receptor inactivation on the leukocyte cell subsets in the blood during CLP.Numbers of total white cell (a), as well as CD11b+ (b), CD19+ (c), and CD3+ (d) cells were monitored in blood by flow cytometric analysis after 16 hours of sepsis induced by CLP. Data are the mean±SEM of n = 6–9 mice per group. *p<0.05; **p<0.01.

Mentions: CLP-challenged mice exhibit a decrease in white blood cell numbers, which includes CD11b+ cells (mostly neutrophils), CD3+ T lymphocytes, and CD19+ B lymphocytes [34], [35]. Unchallenged CB2 KO mice have cell counts comparable to their WT counterparts [36]. Flow-cytometric analysis of cell counts revealed that CLP-challenged CB2 KO mice have increased numbers of total white blood cells (Figure 6a), CD11b+ (Figure 6b) cells and CD19+ B lymphocytes (Figure 6c) in comparison with CB2 WT mice, whereas the number of CD3+ T cells (Figure 6d) was comparable between WT and KO mice undergoing CLP. We propose that preserved white blood cell numbers in KO animals contribute to the decreased bacterial growth and mortality of these mice.


CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis.

Csóka B, Németh ZH, Mukhopadhyay P, Spolarics Z, Rajesh M, Federici S, Deitch EA, Bátkai S, Pacher P, Haskó G - PLoS ONE (2009)

Effect of CB2 receptor inactivation on the leukocyte cell subsets in the blood during CLP.Numbers of total white cell (a), as well as CD11b+ (b), CD19+ (c), and CD3+ (d) cells were monitored in blood by flow cytometric analysis after 16 hours of sepsis induced by CLP. Data are the mean±SEM of n = 6–9 mice per group. *p<0.05; **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712683&req=5

pone-0006409-g006: Effect of CB2 receptor inactivation on the leukocyte cell subsets in the blood during CLP.Numbers of total white cell (a), as well as CD11b+ (b), CD19+ (c), and CD3+ (d) cells were monitored in blood by flow cytometric analysis after 16 hours of sepsis induced by CLP. Data are the mean±SEM of n = 6–9 mice per group. *p<0.05; **p<0.01.
Mentions: CLP-challenged mice exhibit a decrease in white blood cell numbers, which includes CD11b+ cells (mostly neutrophils), CD3+ T lymphocytes, and CD19+ B lymphocytes [34], [35]. Unchallenged CB2 KO mice have cell counts comparable to their WT counterparts [36]. Flow-cytometric analysis of cell counts revealed that CLP-challenged CB2 KO mice have increased numbers of total white blood cells (Figure 6a), CD11b+ (Figure 6b) cells and CD19+ B lymphocytes (Figure 6c) in comparison with CB2 WT mice, whereas the number of CD3+ T cells (Figure 6d) was comparable between WT and KO mice undergoing CLP. We propose that preserved white blood cell numbers in KO animals contribute to the decreased bacterial growth and mortality of these mice.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT

Background: 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.

Methods and findings: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus