Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice

Li, Shanshan; Wang, Linlin; Liu, Min; Jiang, Shenyi; Zhang, Miao; Tian, Zhi-Ling; Wang, Meng; Li, Jiao‐Yong; Zhao, Rui; Guan, Dawei

doi:10.3892/mmr.2016.4961

Cited by 36 publications

(29 citation statements)

References 25 publications

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“… 65 Furthermore, it seems that the activation of CB2 receptors reduces the fibrotic formation in a wound model in mice through the modulation of TGF-β in late stages of the wound healing process. 66 This anti-fibrotic effect mediated by CB2 receptor activation has been confirmed in CB2 receptor knockout mice studies. 67 On the other hand, CB1 receptors activation promotes a fibrotic response in mice.…”

Section: Discussionmentioning

confidence: 76%

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery

et al. 2017

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BackgroundJWH015 is a cannabinoid (CB) receptor type 2 agonist that produces immunomodulatory effects. Since skin cells play a key role in inflammatory conditions and tissue repair, we investigated the ability of JWH015 to promote an anti-inflammatory and pro-wound healing phenotype in human primary skin cells.MethodsHuman primary keratinocytes and fibroblasts were stimulated with lipopolysaccharide. The mRNA expression of cannabinoid receptors was determined using RT-PCR. The effects of JWH015 (0.05, 0.1, 0.5, and 1 µM) in pro- and anti-inflammatory factors were tested in lipopolysaccharide-stimulated cells. A scratch assay, using a co-culture of keratinocytes and fibroblasts, was used to test the effects of JWH015 in wound healing. In addition, the topical and transdermal penetration of JWH015 was studied in Franz diffusion cells using porcine skin and LC-MS.ResultsThe expression of CB1 and CB2 receptors (mRNA) and the production of pro- and anti-inflammatory factors enhanced in keratinocytes and fibroblasts following lipopolysaccharide stimulation. JWH015 reduced the concentration of major pro-inflammatory factors (IL-6 and MCP-1) and increased the concentration of a major anti-inflammatory factor (TGF-β) in lipopolysaccharide-stimulated cells. JWH015 induced a faster scratch gap closure. These JWH015’seffects were mainly modulated through both CB1 and CB2 receptors. Topically administered JWH015 was mostly retained in the skin and displayed a sustained and low level of transdermal permeation.ConclusionsOur findings suggest that targeting keratinocytes and fibroblasts with cannabinoid drugs could represent a therapeutic strategy to resolve peripheral inflammation and promote tissue repair.

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Section: Discussionmentioning

confidence: 76%

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery

et al. 2017

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“…The post-injury treatment of mice was according to previously published methods [ 8 , 22 ]. Briefly, mice that underwent surgery were randomly divided into four groups (vehicle group, JWH133 group, GP1a group, and AM630 group; 25 mice in each group) and administered an i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Several research groups have shown that the selective activation of CB2R can attenuate pro-inflammatory M1 macrophage polarisation and increase anti-inflammatory M2 polarisation [ 18 – 21 ]. However, considering CB2R inhibits fibrosis [ 8 , 22 , 23 ] while M2 promotes fibrosis [ 17 , 24 ], the activation of CB2R to increase levels of M2 macrophages appears contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophage levels.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages

Ren

Wang

et al. 2018

J Inflamm

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BackgroundThe anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation. Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation. However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages.MethodsWe established an incised wound model using mouse skin and used this to evaluate the effect of CB2R agonists (JWH133 or GP1a) and an antagonist (AM630) on wound healing. At various post-injury intervals, we used western blot analysis, immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction assays to determine CB2R protein expression, M1/M2 macrophage infiltration, and the protein and gene expression of M1/M2-associated markers and cytokines in skin lesions.ResultsActivation of CB2R significantly reduced M1 macrophage infiltration and slightly increased M2 macrophage infiltration. Similarly, gene expression and protein levels of M1-associated markers and cytokines (interleukin [IL]-6, IL-12, CD86 and inducible nitric oxide synthase) were significantly down-regulated after CB2R agonist administration; in contrast, markers and cytokines were increased in the CB2R antagonist–treated group. Conversely, the administration of agonists slightly increased gene expression and protein levels of M2-associated markers and cytokines (IL-4, IL-10, CD206 and arginase-1 [Arg-1]); however, a statistical significance at most time points post-injury was not noted.ConclusionIn summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation. These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.

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“…In contrast, the activation of cannabinoid receptor 2 (CB2R), a specific metabotropic receptor of the endocannabinoid system (ECS), reduces inflammation in cerebral ischemic injury, acute myocardial infarction, nephropathy, and cystitis 14 – 17 . Moreover, CB2R activation also attenuates hepatic and skin fibrosis in mouse models 18 , 19 . Activating of CB2R with agonist inhibits the development of renal fibrosis, and a CB2R antagonist blunts this beneficial anti-fibrotic effect in a unilateral ureteral obstruction (UUO) mouse model 20 .…”

Section: Introductionmentioning

confidence: 97%

Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression

et al. 2018

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Renal fibrosis is the final manifestation of various chronic kidney diseases, and no effective therapy is available to prevent or reverse it. Celastrol, a triterpene that derived from traditional Chinese medicine, is a known potent anti-fibrotic agent. However, the underlying mechanisms of action of celastrol on renal fibrosis remain unknown. In this study, we found that celastrol treatment remarkably attenuated unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis. This was evidenced by the significant reduction in tubular injury; collagen deposition; accumulation of fibronectin, collagen I, and α-smooth muscle actin; and the expression levels of pro-fibrotic factors Vim, Cola1, and TGF-β1 mRNA, as well as inflammatory responses. Celastrol showed similar effects in a folic acid-induced mouse renal fibrosis model. Furthermore, celastrol potentiated the expression of the anti-fibrotic factor cannabinoid receptor 2 (CB2R) in established mouse fibrotic kidney tissues and transforming growth factor β1 (TGF-β1)-stimulated human kidney 2 (HK-2) cells. In addition, the CB2R antagonist (SR144528) abolished celastrol-mediated beneficial effects on renal fibrosis. Moreover, UUO- or TGF-β1-induced activation of the pro-fibrotic factor SMAD family member 3 (Smad3) was markedly inhibited by celastrol. Inhibition of Smad3 activation by an inhibitor (SIS3) markedly reduced TGF-β1-induced downregulation of CB2R expression. In conclusion, our study provides the first direct evidence that celastrol significantly alleviated renal fibrosis, by contributing to the upregulation of CB2R expression through inhibiting Smad3 signaling pathway activation. Therefore, celastrol could be a potential drug for treating patients with renal fibrosis.

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Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice

Cited by 36 publications

References 25 publications

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery

Cannabinoid 2 receptor attenuates inflammation during skin wound healing by inhibiting M1 macrophages rather than activating M2 macrophages

Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression

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