Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Mai, Ping; Yang, Le; Tian, Lei; Wang, Lin; Jia, Shuangshuang; Zhang, Yuanyuan; Liu, Xin; Yang, Lin; Li, Liying

doi:10.4049/jimmunol.1403205

Cited by 37 publications

(60 citation statements)

References 48 publications

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“…LH-21 did not affect the number of repairer M2 macrophages in any tissue, thus suggesting that beneficial actions of LH-21 in the liver might be mediated through downregulation of killer M1 macrophages. In agreement with our findings, lower levels of cleaved caspase-3 have been found in islets of streptozotocin -injected mice after treatment with the CB1 antagonist/inverse agonist AM251 19 and CB1 in macrophages has also been linked to both islet and liver damage 20, 21 . However, the reason for the differential response between these two tissues is unknown and could be related to the level of expression and/or the specific cell type expressing the target receptor.…”

Section: Discussionsupporting

confidence: 93%

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice

Romero-Zerbo

Ruz‐Maldonado

Espinosa-Jímenez

et al. 2017

Sci Rep

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LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.

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Section: Discussionsupporting

confidence: 93%

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice

Romero-Zerbo

Ruz‐Maldonado

Espinosa-Jímenez

et al. 2017

Sci Rep

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“…Blockade of S1PR 3 by antagonist or knockout limits the accumulation of peritoneal macrophage cells in the inflamed site in vivo [45]. Our previous studies have shown that the BMMs played a crucial role in BDL-or CCl 4 -induced liver disease [20,29]. Inhibition of S1PR 2/3 depressed M1 mobility and thus attenuated the inflammation and liver fibrosis in injured liver [20].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that recruitment of BMMs in the injured liver could aggravate liver inflammation and thus played a crucial role in BDL-or CCl 4 -induced liver disease [20,29,30]. Among a variety of factors that mediate switch BMMs to pro-inflammatory M1 phenotype, S1P is probably one of the most potent regulatory molecules [36].…”

Section: Discussionmentioning

confidence: 99%

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Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway

Yang¹,

Yang²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Macrophages, the most plastic cells in the haematopoietic system, are found in all tissues and show great functional heterogeneity. Sphingosine 1-phosphate (S1P)/ S1P receptors (S1PRs) system is widely involved in the process of inflammatory disease, whereas little evidence concerning its role in functional macrophage polarization is available. Thus, the present study was designed to evaluate the effects of S1P/S1PRs on functional polarization of macrophage in mouse bone marrow (BM)-derived monocyte/macrophages (BMMs). Methods: For the detection of M1 macrophage markers, such as CD86, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1/ chemokine (C-C motif) ligand (CCL) 2, nitric oxide synthase (NOS) 2, and macrophage inflammatory protein (MIP)-1β, RT-qPCR and cytometric bead array (CBA) were performed in cultured primary BMMs after the treatment with selective S1PR_2/3 antagonists or specific S1PRs siRNA. Western blotting and immunofluorescence were used for the detection of phosphorylation of JNK1/2. Results: BMMs expressed S1PR_1-3 and interestingly, S1PR_2/3, but not S1PR₁, mediates S1P-induced M1 macrophage polarization of BMMs as their siRNA or antagonists reduced M1 genes’ expression. We found that PTX (inhibitor of G(α)_i/o), LY294002 (inhibitor of PI3K) or SP600125 (inhibitor of JNK1/2) prevented up-regulation of M1 genes expression mediated by S1P/S1PR_2/3 signal, and S1P-induced JNK phosphorylation was inhibited by antagonists of S1PR_2/3, PTX or LY294002. Conclusion: Collectively, our results demonstrate that S1P/S1PR_2/3 plays a key role in regulating M1 type polarization of BMMs and acts by activating G(α)_i/o/PI3K/JNK signaling pathway, with potential implications for new approaches to inflammatory liver disease therapy.

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“…It has been recently shown through in vitro and animal studies that the cannabinoid receptor 1 (CB-1) contributes to liver injury, inflammation and may be involved in the initiation of hepatocellular carcinoma through endocannabinoid system activation [1, 2]. Endogenous cannabinoids (EC) have been shown to be closely related to fatty liver metabolism [3, 4], modulating lipid metabolism and contributing to non-alcoholic fatty liver disease development (NAFLD) through [5] that may be ameliorated by CB1 receptor antagonism with antagonists such as rimonabant [5].…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss

et al. 2017

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BackgroundEvidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile.MethodsPost hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD).ResultsTreatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT.ConclusionRimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD.Trial registrationISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

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Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Cited by 37 publications

References 48 publications

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice

The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice

Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway

Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss

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