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Cannabinoid receptor 2 protects against acute experimental sepsis in mice
Huan Gui1, Yang Sun, Zhu-Min Luo
1Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Abstract:
The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R(-/-)). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R(-/-) splenocytes but completely abolished in CB2R(-/-) peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I κ B α degradation and NF- κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.
Insights
Cannabinoid receptor 2 (CB2R) activation protects against sepsis. Targeting CB2R may offer a novel therapeutic strategy for treating sepsis and reducing mortality.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Sepsis remains a critical clinical challenge despite advances in understanding its mechanisms.
- The role of cannabinoid receptor 2 (CB2R) in sepsis pathophysiology is currently undefined.
- Systemic inflammatory response syndrome can progress to severe sepsis and septic shock.
Purpose of the Study:
- To investigate the role and mechanism of CB2R in a mouse model of acute sepsis.
- To evaluate the therapeutic potential of CB2R agonists in sepsis treatment.
Main Methods:
- Utilized CB2R knockout (CB2R(-/-)) mice and lipopolysaccharide (LPS) to induce sepsis.
- Administered a CB2R agonist (GW405833) to assess its effects on survival and inflammation.
- Analyzed cytokine levels, splenocyte proliferation, and macrophage signaling pathways (ERK1/2, STAT3, NF-κB).
Main Results:
- CB2R deletion exacerbated LPS-induced mortality and inflammation in mice.
- GW405833 treatment significantly improved survival and reduced pro-inflammatory cytokines in LPS-treated mice.
- GW405833 inhibited cytokine release and splenocyte proliferation, with effects dependent on CB2R expression in immune cells.
- GW405833 modulated key inflammatory signaling pathways, including ERK1/2, STAT3, and NF-κB.
Conclusions:
- CB2R plays a protective role in acute sepsis.
- Activation of CB2R demonstrates therapeutic potential for sepsis.
- CB2R represents a promising therapeutic target for managing sepsis.
