Cannabinoid Receptor 1/miR-30b-5p Axis Governs Macrophage NLRP3 Expression and Inflammasome Activation in Liver Inflammatory Disease

Abstract

Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) has been regarded as an important initiator or promoter in multiple inflammatory diseases. However, the relationship between cannabinoid receptor 1 (CB1) and macrophage NLRP3 inflammasome and the corresponding molecular mechanism in liver inflammation remain unclear. Mouse liver injury models were induced by carbon tetrachloride (CCl 4 ) or methionine-choline-deficient and high fat (MCDHF) diet. Human liver tissues were obtained from patients with different chronic liver diseases. CB1 expression was increased in liver tissue and macrophages of CCl 4 -and MCDHF-treated mice, positively correlated with NLRP3. CB1 agonist ACEA (Arachiodonyl-2'-Chloroethylamide) promoted NLRP3 expression and NLRP3 inflammasome activation in macrophages. CB1 blockade with its antagonist AM281 reduced NLRP3 expression, inflammasome activation, and liver inflammation in CCl 4 -and MCDHF-treated mice. MicroRNA-30b-5p (miR-30b-5p), screened by the intersection of bioinformatics databases and downregulated miRNAs in injured liver, negatively correlated with NLRP3 in mouse and human liver. miR-30b-5p was involved in CB1-mediated activation of NLRP3 inflammasome in macrophages by directly targeting NLRP3. Importantly, administration of miR-30b-5p agomir targeted NLRP3 and attenuated liver inflammation in the injured liver. Altogether, CB1/miR-30b-5p axis modulates NLRP3 expression and NLPR3 inflammasome activation in macrophages during liver inflammation, which provides a potential target for liver disease.

Mechanism of miR-30b-5p-Loaded PEG-PLGA Nanoparticles for Targeted Treatment of Heart Failure

“… Liu et al (2017) identified miR-30b-5p as a novel tumour suppressor that regulates renal cell carcinoma cell proliferation, metastasis, and epithelial mesenchymal transition (EMT) by downregulating GNA13 expression. In addition, therapeutic effects have also been reported in gliomas ( Qin et al, 2017 ), inflammatory diseases ( Yang et al, 2020 ), liver cancer ( Qin et al, 2017 ; Zhang et al, 2020 ), and other diseases. We found that there was a binding site of miR-30b-5p with TGFBR2 using bioinformatics software as well as dual luciferase activity assay experiments.…”

The Potential Use of Cannabis in Tissue Fibrosis

“…When miR-30b-5p agomir was administered, it targeted NLRP3 and mitigated liver inflammation. These results suggested that CB1/miR-30b-5p axis is able to modulate the activation of NLRP3 inflammasome and expression of NLRP3 in macrophages in liver inflammatory disease ( Yang et al, 2020 ).…”

Expression, Regulation and Functions of MicroRNAs in Autoimmune Hepatitis

“…Thus, miR-30b-5p may be involved in the progression from liver fibrosis to cirrhosis. In addition, miR-30b-5p could target Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) and thus inhibit liver inflammation in the injured liver [75]. Therefore, miR-30b-5p may play a role in AIH pathogenesis.…”