Peroxisome proliferator–activated receptor γ–mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice

Jung, Kyungsook; Tanaka, Akane; Fujita, Hiroshi; Matsuda, Akihisa; Oida, Kumiko; Karasawa, Kaoru; Okamoto, Nobuhiko; Ohmori, Kitaro; Jee, Youngheun; Shin, Taekyun; Matsuda, Hiroshi

doi:10.1016/j.jaci.2010.10.043

Cited by 45 publications

(38 citation statements)

References 59 publications

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“…More recently, we have demonstrated that TSLP released from keratinocytes of the skin lesions (Fig. 2D) contributes to the early onset of AD in NC/Tnd mice through the maturation and migration of DCs in the skin and also found that the ignition of peroxisome proliferator-activated receptor gamma with a synthetic agonist reduces the onset of AD via inhibition of dendritic cell functions activated by TSLP [7]. Researchers have to be careful because there are some sublines of NC strains that rarely develop AD spontaneously.…”

Section: Spontaneous Model For Ad Nc/tnd Micementioning

confidence: 87%

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Recent Findings in Mouse Models for Human Atopic Dermatitis

et al. 2012

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Atopic dermatitis (AD) is a chronic inflammatory skin disease, with its major clinical feature being persistent itch sensation in the skin. There are extremely few animal models to reproduce the complicated condition of a patient with AD; therefore researchers have been confronted with some difficulties in pathologic analysis and drug development for AD. Although various models have been proposed and developed, there is no doubt that the spontaneous mouse model, NC mice, gave the greatest impact. NC mice enabled us to analyze pathogenesis of allergic skin abnormalities as well as development of new drugs for AD. However, many questions still remain in the pathogenesis of AD. In recent years, the study of the itch has attracted our attention because itch is one of the most unbearable symptoms of AD. For development of an effective treatment to overcome the itch, not only a precise animal model but also an accurate evaluation protocol are needed. This review summarizes some mouse models of AD, particularly focusing on NC mice, together with a novel evaluation system for scratching behavior of mice to help the understanding of researchers.

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Section: Spontaneous Model For Ad Nc/tnd Micementioning

confidence: 87%

“…SCLABA-Real ® enabled us to analyze scratching behavior in real-time without using any kinds of stressful operations on a mouse (Fig. 3) [7]. The behavior of 4 mice is simultaneously recorded with a high-speed digital camera from the top of individual cages placed on invisible near-infrared light.…”

Section: Attempt To Evaluate Scratching Behavior In Micementioning

confidence: 99%

Recent Findings in Mouse Models for Human Atopic Dermatitis

et al. 2012

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“…1 We should mention that factors reported to signal through pathways different from cAMP also induce Mmp9 expression in DCs. 24,50 If these alternative pathways occur in vivo, the MMP-9-dependent migration of activated DCs might not be affected by CB2R signaling. However, the studies mentioned above did not address the possibility of endogenous PGE2 generation especially in an inflammatory milieu.…”

Section: Discussionmentioning

confidence: 99%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

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Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs. IntroductionThe cannabinoid system consists of cannabinoid receptors and their ligands, including endocannabinoids, synthetic cannabinoid receptor agonists and antagonists, and phytocannabinoids. Several cannabinoid receptors have been described, that is, the classic cannabinoid receptor 1 (GPR) and GPR, the previously orphaned G-protein receptors GPR18 and GPR55, various ion channels, and intracellular peroxisome proliferator-activated receptor-␥ (reviewed in Pertwee et al 1 and Console-Bram 2 ). The 2 classic cannabinoid receptors, CB1R and CB2R, have different distribution and functions (reviewed in Kubajewska and Constantinescu 3 and Basu and Dittel 4 ). CB1R is abundantly expressed on CNS and peripheral neurons and involved in neural functions. In contrast, CB2R is mostly expressed on immune cells and involved in immunoregulation. Administration of CB2R-selective agonists in models of inflammatory and autoimmune diseases such as systemic sclerosis, experimental autoimmune uveoretinitis, inflammatory bowel diseases, and experimental autoimmune encephalomyelitis (EAE) resulted in attenuation of clinical disease (reviewed in Basu and Dittel 4 ). CB2R agonists also have been reported to have a beneficial effect in models of CNS injury such as cerebral infarction and spinal cord injury. [5][6][7][8] In addition to effects on clinical outcome, CB2R agonists reduced the levels of inflammatory mediators in various experimental models. [8][9][10] A possible mechanism for the anti-inflammatory effect of CB2R signaling is the direct action of CB2R agonists on immune cells. In vitro studies indicated that CB2R signaling inhibited the production of proinflammatory cytokines such as TNF␣, IL-6, IL-2, and IFN-␥ by ac...

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“…Therefore, we aimed at investigating (i) mRNA and protein expressions and activity of FAAH in human keratinocytes in Toll-like receptor (TLR)-induced inflammation models and (ii) the suggested anti-inflammatory effects of two newly developed, potent and selective N-alkylcarbamate FAAH inhibitors WOBE440 (IC 50 = 25 AE 8 nM) and WOBE479 (IC 50 = 78 AE 13 nM) (Fig. S1) which show high specificity over other known targets within the ECS [IC 50 > 10 lM for cannabinoid receptor (CNR)-1, CNR2, monoacylglycerol lipase and the putative endocannabinoid membrane transporter] (6) on primary (NHEK) and immortalized (HPV-KER) (7,8) human epidermal keratinocytes as well as in NC/Tnd mice, a widely used animal model of atopic dermatitis (AD) (9).…”

Section: Questions Addressedmentioning

confidence: 99%

Inhibition of fatty acid amide hydrolase exerts cutaneous anti‐inflammatory effects both in vitro and in vivo

Oláh

Ambrus

Nicolussi

et al. 2016

Experimental Dermatology

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BackgroundNumerous studies introduced epidermal keratinocytes as 'nonclassical' immune-competent cells, hence potent primary regulators and active participants of cutaneous immune functions (1), (s1-6). Therefore, targeting them might provide a novel, highly specific anti-inflammatory therapeutic possibility. The endocannabinoid system (ECS) is an emerging signalling network which regulates multiple cutaneous functions (2,3). The loss of homoeostatic endocannabinoid (eCB) signalling of epidermal keratinocytes was shown to dramatically enhance inflammatory processes, arguing for that the cutaneous eCB tone plays a 'gatekeeper' role in the initiation phase of skin inflammation (4); for further details see Supplementary Background section). Moreover, elevation of the eCB tone, for example by the inhibition of fatty acid amide hydrolase (FAAH), the most important enzyme engaged with the degradation of the eCB anandamide (AEA); (5), exerts ECS-mediated anti-inflammatory actions in multiple organs (5). Questions addressedBased on these data, we hypothesized that upregulation of expression/activity of FAAH [thereby decreasing the eCB tone, and increasing the level of the pro-inflammatory 'eCB degradation product' arachidonic acid (AA)] might contribute to the development of the inflammatory processes. Therefore, we aimed at investigating (i) mRNA and protein expressions and activity of FAAH in human keratinocytes in Toll-like receptor (TLR)-induced inflammation models and (ii) the suggested anti-inflammatory effects of two newly developed, potent and selective N-alkylcarbamate FAAH inhibitors WOBE440 (IC 50 = 25 AE 8 nM) and WOBE479 (IC 50 = 78 AE 13 nM) (Fig. S1) which show high specificity over other known targets within the ECS [IC 50 > 10 lM for cannabinoid receptor (CNR)-1, CNR2, monoacylglycerol lipase and the putative endocannabinoid membrane transporter] (6) on primary (NHEK) and immortalized (HPV-KER) (7,8) human epidermal keratinocytes as well as in NC/Tnd mice, a widely used animal model of atopic dermatitis (AD) (9).

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Peroxisome proliferator–activated receptor γ–mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice

Cited by 45 publications

References 59 publications

Recent Findings in Mouse Models for Human Atopic Dermatitis

Recent Findings in Mouse Models for Human Atopic Dermatitis

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Inhibition of fatty acid amide hydrolase exerts cutaneous anti‐inflammatory effects both in vitro and in vivo

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