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The Cannabinoid Receptor 2 Is Critical for the Host Response to Sepsis

Johannes Tschöp^*,, Kevin R. Kasten^*, Ruben Nogueiras, Holly S. Goetzman^*, Cynthia M. Cave^*, Lisa G. England^*,, Jonathan Dattilo^*, Alex B. Lentsch^*, Matthias H. Tschöp and Charles C. Caldwell^*,

^*The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Department of Research, Shriner’s Hospital for Children, Cincinnati, OH 45229; Department of Psychiatry, Obesity Research Centre-Genome Research Institute, University of Cincinnati, Cincinnati, OH 45226; and Department of Anesthesiology, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany

Leukocyte function can be modulated through the cannabinoid receptor 2 (CB2R). Using a cecal ligation and puncture (CLP) model of sepsis, we examined the role of the CB2R during the immune response to an overwhelming infection. CB2R-knock out (KO) mice showed decreased survival as compared with wild-type mice. CB2R-KO mice also had increased serum IL-6 and bacteremia. Twenty-four hours after CLP, the CB2R-deficient mice had increased lung injury. Additionally, CB2R-deficiency led to increased neutrophil recruitment, decreased neutrophil activation, and decreased p38 activity at the site of infection. Consistent with a novel role for CB2R in sepsis, CB2R-agonist treatment in wild-type mice increased the mean survival time in response to CLP. Treatment with CB2R-agonist also decreased serum IL-6 levels, bacteremia, and damage to the lungs compared with vehicle-treated mice. Finally, the CB2R agonist decreased neutrophil recruitment, while increasing neutrophil activation and p38 activity at the site of infection compared with vehicle-treated mice. These data suggest that CB2R is a critical regulator of the immune response to sepsis and may be a novel therapeutic target.

Address correspondence and reprint requests to Dr. Charles C. Caldwell, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Medical Science Building,Surgical Research Unit G479 ML 0558, Cincinnati, OH 45267-0558. E-mail address:charles.caldwell{at}uc.edu

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