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

Balázs Csóka, Zoltán H. Németh, Partha Mukhopadhyay, Zoltán Spolarics, Mohanraj Rajesh, Stephanie Federici, Edwin A. Deitch, Sándor Bátkai, Pál Pacher, G. Haskó

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 CB2 receptors on immune cells. Here we examined the role of CB2 receptors in regulating the host's response to sepsis. Methods and Findings: The role of CB2 receptors was studied by subjecting CB2 receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB2 receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB2 receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-κB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB2 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 CB2 receptors are important contributors to septic immune dysfunction and mortality, indicating that CB2 receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.

Original languageEnglish
Article numbere6409
JournalPLoS One
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 29 2009

Fingerprint

Cannabinoid Receptor CB2
sepsis (infection)
Sepsis
receptors
Mortality
inactivation
cannabinoid receptors
Endocannabinoids
Bacterial Translocation
cells
interleukin-10
Immune system
interleukin-6
Pathogens
health services
blood flow
immune system
GTP-Binding Proteins
Interleukin-10
G-Protein-Coupled Receptors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Csóka, B., Németh, Z. H., Mukhopadhyay, P., Spolarics, Z., Rajesh, M., Federici, S., ... Haskó, G. (2009). CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. PLoS One, 4(7), [e6409]. https://doi.org/10.1371/journal.pone.0006409

CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. / Csóka, Balázs; Németh, Zoltán H.; Mukhopadhyay, Partha; Spolarics, Zoltán; Rajesh, Mohanraj; Federici, Stephanie; Deitch, Edwin A.; Bátkai, Sándor; Pacher, Pál; Haskó, G.

In: PLoS One, Vol. 4, No. 7, e6409, 29.07.2009.

Research output: Contribution to journalArticle

Csóka, B, Németh, ZH, Mukhopadhyay, P, Spolarics, Z, Rajesh, M, Federici, S, Deitch, EA, Bátkai, S, Pacher, P & Haskó, G 2009, 'CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis', PLoS One, vol. 4, no. 7, e6409. https://doi.org/10.1371/journal.pone.0006409
Csóka B, Németh ZH, Mukhopadhyay P, Spolarics Z, Rajesh M, Federici S et al. CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. PLoS One. 2009 Jul 29;4(7). e6409. https://doi.org/10.1371/journal.pone.0006409
Csóka, Balázs ; Németh, Zoltán H. ; Mukhopadhyay, Partha ; Spolarics, Zoltán ; Rajesh, Mohanraj ; Federici, Stephanie ; Deitch, Edwin A. ; Bátkai, Sándor ; Pacher, Pál ; Haskó, G. / CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. In: PLoS One. 2009 ; Vol. 4, No. 7.
@article{f1251ba2b0ae4df59b54cd20a6594c6c,
title = "CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis",
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 CB2 receptors on immune cells. Here we examined the role of CB2 receptors in regulating the host's response to sepsis. Methods and Findings: The role of CB2 receptors was studied by subjecting CB2 receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB2 receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB2 receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-κB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB2 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 CB2 receptors are important contributors to septic immune dysfunction and mortality, indicating that CB2 receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.",
author = "Bal{\'a}zs Cs{\'o}ka and N{\'e}meth, {Zolt{\'a}n H.} and Partha Mukhopadhyay and Zolt{\'a}n Spolarics and Mohanraj Rajesh and Stephanie Federici and Deitch, {Edwin A.} and S{\'a}ndor B{\'a}tkai and P{\'a}l Pacher and G. Hask{\'o}",
year = "2009",
month = "7",
day = "29",
doi = "10.1371/journal.pone.0006409",
language = "English",
volume = "4",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis

AU - Csóka, Balázs

AU - Németh, Zoltán H.

AU - Mukhopadhyay, Partha

AU - Spolarics, Zoltán

AU - Rajesh, Mohanraj

AU - Federici, Stephanie

AU - Deitch, Edwin A.

AU - Bátkai, Sándor

AU - Pacher, Pál

AU - Haskó, G.

PY - 2009/7/29

Y1 - 2009/7/29

N2 - 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 CB2 receptors on immune cells. Here we examined the role of CB2 receptors in regulating the host's response to sepsis. Methods and Findings: The role of CB2 receptors was studied by subjecting CB2 receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB2 receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB2 receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-κB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB2 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 CB2 receptors are important contributors to septic immune dysfunction and mortality, indicating that CB2 receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.

AB - 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 CB2 receptors on immune cells. Here we examined the role of CB2 receptors in regulating the host's response to sepsis. Methods and Findings: The role of CB2 receptors was studied by subjecting CB2 receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB2 receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB2 receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-κB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB2 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 CB2 receptors are important contributors to septic immune dysfunction and mortality, indicating that CB2 receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.

UR - http://www.scopus.com/inward/record.url?scp=68149166272&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68149166272&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0006409

DO - 10.1371/journal.pone.0006409

M3 - Article

C2 - 19641602

AN - SCOPUS:68149166272

VL - 4

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e6409

ER -