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

Abstract

BackgroundSepsis 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 FindingsThe 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.ConclusionsTaken 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.

Cannabinoid Receptor 2 Suppresses Leukocyte Inflammatory Migration by Modulating the JNK/c-Jun/Alox5 Pathway

“…It has been shown that Cnr2 signaling and the Alox5 pathway are both involved in the regulation of leukocyte migration (22)(23)(24). Previous studies showed that cannabidiol inhibits tumor cell growth by down-regulating the activity and expression of Alox5 (38), and it was also shown that there is a cooperative antineurotoxic effect between a selective Cnr2 agonist (JWH-015) and a specific Alox5 inhibitor (REV 5901) in THP-1 cells in vitro (56).…”

“…Cnr1 is highly expressed in the central nervous system and less in peripheral tissues (19), while Cnr2 is predominantly expressed in cells of hematopoietic origin in both mice and humans (20,21). Previous studies of the human and mouse cannabinoid system have shown that Cnr2 modulates the inflammatory migration of immune cells through many pathways and participates in the progression of many important autoimmune diseases (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). To confirm our chemical genetic screening, we generated mutant alleles of zebrafish cnr2 (gene encoding Cnr2) and found that leukocyte migration is enhanced by the inactivation of Cnr2, further confirming that Cnr2 acts as a conserved negative inflammatory regulator in the vertebrate.…”

2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV

“…Moreover, inconsistencies are found regarding the expression of the CB receptors [27,36,56,57,[69][70][71][72][73][74][75][76][77]. Importantly, studies that reported a lack of CB 2 were performed using cell preparations in which contaminating eosinophils were removed [27,36].…”

Targeting the Endocannabinoid System to Treat Sepsis

“…(35) However, research on the modulation of these receptors has also provided some contradictory results. (36,37) A study by Tschöp et al modulated the CB 2 receptor in a systemic septic model induced through cecal ligation and puncture (CLP) in mice. (36) They observed reduced survival time of CB 2 receptor knockout mice compared to wild type mice during systemic sepsis.…”

“…All of these results indicated that CB 2 receptor activation during systemic sepsis increased IL-10 overproduction causing an increase in bacterial invasion into the blood, ultimately resulting in increased mortality rates. (37) Multiple factors may help explain the inconsistency reported in studies of manipulating the CB 2 receptor during a septic state. (36,37) A possible explanation could be the severity of sepsis, where certain factors may play a crucial role in determining the role of the endocannabinoid receptors.…”