Activation of cannabinoid receptors 2 alleviates myocardial damage in cecal ligation and puncture-induced sepsis by inhibiting pyroptosis

Immunol Lett. 2023 Dec:264:17-24. doi: 10.1016/j.imlet.2023.10.007. Epub 2023 Nov 2.

Abstract

Background: It has been reported that cannabinoid receptors 2 (CB2 receptors) play an important role in the pathophysiological process of sepsis, which may also be associated with the regulation of pyroptosis, an inflammatory programmed cell death. The present study aimed to investigate the protective effect of CB2 receptors on myocardial damage in a model of septic mice by inhibiting pyroptosis.

Methods: The C57BL/6 mice underwent cecal ligation and puncture (CLP) to induce sepsis. All mice were randomly divided into the sham, CLP, or CLP+HU308 group. Blood and heart tissue samples were collected 12 h after surgery. Hematoxylin and eosin staining was used for analyzing histopathological results. Creatine kinase isoenzymes (CK-MB) and IL-1β were measured using ELISA, while lactate dehydrogenase (LDH) level was determined using photoelectric colorimetry. The expression levels of CB2 receptors and pyroptosis-associated proteins (NLRP3, caspase-1, and GSDMD) were measured using western blotting. The location and distribution of CB2 receptors and caspase-1 in myocardial tissues were assessed by immunofluorescence. TUNEL staining was used to quantify the number of dead cells in myocardial tissues.

Results: The CLP procedure increased CB2 receptor expression in mice. CB2 receptors were located in myocardial macrophages. Activating CB2 receptors decreased the levels of myocardial damage mediator LDH, CK-MB, and inflammatory cytokine IL-1β. The results also showed that CLP increased the pyroptosis in myocardial tissues, while CB2 agonist HU308 inhibited pyroptosis by decreasing the level of NLRP3 and activating caspase-1 and GSDMD.

Conclusions: CB2 receptor activation has a protective effect on the myocardium of mice with sepsis by inhibiting pyroptosis.

Keywords: Cannabinoid receptor 2; Myocardial damage; Pyroptosis; Sepsis.

MeSH terms

  • Animals
  • Caspases / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Punctures
  • Pyroptosis
  • Receptor, Cannabinoid, CB2
  • Sepsis* / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • HU 308
  • Receptor, Cannabinoid, CB2
  • Caspases