Resolvin D1 attenuates imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-κB pathways.

Resolvin D1 (RvD1), a pro-resolution lipid mediator derived from docosahexaenoic acid (DHA), has been described to promote several kinds of inflammatory resolution. However, the effects and anti-inflammatory mechanisms of RvD1 on psoriasis have not been previously reported. The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on imiquimod (IMQ)-induced psoriasiform dermatitis. Mice were topically treated with IMQ to develop psoriasiform dermatitis on their shaved back, pretreated intraperitoneally (i.p.) with or without RvD1 or tert-butoxycarbonyl Met-Leu-Phe peptide (Boc), a lipoxin A4 (ALX) receptor antagonist. The severity was monitored and graded using a modified human scoring system, the Psoriasis Area and Severity Index (PASI), histopathology, and the signature cytokines of psoriasis (IL-23, IL-17, IL-22 and TNF-α). The mRNA and protein levels of inflammatory cytokines were quantified by quantitative real-time PCR (QRT-PCR) and ELISA. The expressions of signaling proteins MAPKs and NF-κB p65 were analyzed using western blotting. Electrophoretic mobility shift assay (EMSA) was used to check NF-κB p65 DNA binding activity. Our study showed that RvD1 alleviated IMQ-induced psoriasiform dermatitis and improved skin pathological changes. RvD1 markedly inhibited IMQ-induced activation of ERK1/2, p38, JNK (c-Jun N-terminal protein kinase, a subfamily of MAPKs), and NF-κB. Furthermore, pretreatment with Boc, would not exacerbate skin inflammation of IMQ-induced mice, but significantly reversed the beneficial effects of RvD1 on IMQ-induced psoriasiform inflammation. RvD1 can obviously improve skin inflammation in IMQ-induced mice psoriasiform dermatitis. The protective mechanisms might be related to its selective reaction with lipoxin A4 receptor/Formyl-peptide receptor 2 (ALX/FPR2), by downregulating relevant cytokines of the IL-23/IL-17 axis expression, the inhibition of MAPKs and NF-κB signaling transduction pathways. Thus, these results show that RvD1 could be a possible candidate for psoriasis therapy.

Xu J ，Duan X ，Hu F ，Poorun D ，Liu X ，Wang X ，Zhang S ，Gan L ，He M ，Zhu K ，Ming Z ，Chen H ... -  《-》

Ginsenoside Rg1 abolish imiquimod-induced psoriasis-like dermatitis in BALB/c mice via downregulating NF-κB signaling pathway.

This animal experiment was framed to evaluate the beneficial effect of ginsenoside Rg1 (GRg1) against imiquimod (IMQ)-induced psoriasis-like dermatitis model to reveal the underpinning mechanism. Fifty healthy BALB/c mice were divided into five groups as control, GRg1, IMQ induced, oral treatment of GRg1 (50 mg/kg), or dexamethasone (DXM; 10 mg/kg) in IMQ-induced mice. Treatment with GRg1 or DXM significantly mitigates (p < .01) psoriasis area severity index (PASI) score, skin thickness, lipid peroxidation, and inflammatory markers (IL-23, 22, 17A, 1β, and TNF-α). Moreover, administration of GRg1 or DXM considerably reversed the morphological changes induced by IMQ with improved (p < .01) antioxidant activity (SOD, CAT). In addition, a marked downregulation (p < .01) of protein expressions of pIκB and NF-κB p65 (NF-κB signaling pathway) were noted in GRg1 group. Collectively, GRg1 or DXM treatment significantly abolishes IMQ-induced psoriasis-like dermatitis by lowering PASI score, inflammation through downregulating NF-κB signaling pathway. PRACTICAL APPLICATIONS: This is the very first study to explore the efficacy of ginsenoside Rg1 (GRg1) against IMQ-induced psoriasis in the mice model to reveal the underpinning mechanism. The results clearly showed that GRg1 potent anti-psoriasis activity by lowering PASI score, inflammation through downregulating NF-κB signaling pathway. Hence, this study helps in the development of novel nutraceutical/functional food against psoriasis and thus could improve the quality of life in psoriasis patients. However, further clinical trials are needed to justify the above results before developing a commercial functional food using GRg1 against psoriasis.

Shi Q ，He Q ，Chen W ，Long J ，Zhang B ... -  《-》

Protectin D1 reduces imiquimod-induced psoriasiform skin inflammation.

Specialized proresolving mediators are enzymatically oxygenated natural molecules derived from polyunsaturated fatty acids and are considered novel. These novel mediators include lipoxins from arachidonic acid, resolvins and protectins from omega-3 essential fatty acids, and new maresins. These mediators harbor potent dual proresolving and anti-inflammatory properties. Resolvins and protectins are known to be potent when administered to various inflammation-associated animal models of human diseases. Although psoriasis' etiology remains unknown, there is accumulating evidence indicating that cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17, play pivotal roles in its development. Experimentally, resolvins, maresins, and lipoxins downregulate the cytokine expression of the IL-23/IL-17 axis and inhibition of mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) cell signaling transduction pathways. Here, we assessed the effects of protectin D1 (PD1) on imiquimod (IMQ)-induced psoriasiform skin inflammation and keratinocytes. PD1 showed clinical improvement in skin thickness, redness, and scaling in psoriasis mouse models. Moreover, PD1 decreased IL-1β, IL-6, IL-17, and CXCL1 mRNA expressions and reduced STAT1 and NF-κB signaling pathway activation in lesions. Serum myeloperoxidase, IgG2a, IL-1β, IL-6, IL-17, and TNF-α and spleen CD4+IFN-γ+IL-17+ T lymphocytes were reduced after PD1 treatment in IMQ-induced psoriasiform mouse models. In addition, IL-1β, IL-6, IL-8, and IL-18BP gene expressions were decreased in PD1-treated keratinocytes. Moreover, a decrease in the expression levels of CCL17 and IL-6 and an inhibition of the STAT1 and NF-κB signaling transduction pathways was observed in keratinocytes. These PD1 anti-inflammatory effects suggest that it is a good therapeutic candidate for psoriasis.

Park KD ，Kim N ，Kang J ，Dhakal H ，Kim JY ，Jang YH ，Lee WJ ，Lee SJ ，Kim SH ... -  《-》

Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway.

Quercetin (QC) is a dietary flavonoid abundant in many natural plants. A series of studies have shown that it has been shown to exhibit several biological properties, including anti-inflammatory, anti-oxidant, cardio-protective, vasodilatory, liver-protective and anti-cancer activities. However, so far the possible therapeutic effect of QC on psoriasis has not been reported. The present study was undertaken to evaluate the potential beneficial effect of QC in psoriasis using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, and to further elucidate its underlying mechanisms of action. Effects of QC on PASI scores, back temperature, histopathological changes, oxidative/anti-oxidative indexes, pro-inflammatory cytokines and NF-κB pathway in IMQ-induced mice were investigated. Our results showed that QC could significantly reduce the PASI scores, decrease the temperature of the psoriasis-like lesions, and ameliorate the deteriorating histopathology in IMQ-induced mice. Moreover, QC effectively attenuated levels of TNF-α, IL-6 and IL-17 in serum, increased activities of GSH, CAT and SOD, and decreased the accumulation of MDA in skin tissue induced by IMQ in mice. The mechanism may be associated with the down-regulation of NF-κB, IKKα, NIK and RelB expression and up-regulation of TRAF3, which were critically involved in the non-canonical NF-κB pathway. In conclusion, our present study demonstrated that QC had appreciable anti-psoriasis effects in IMQ-induced mice, and the underlying mechanism may involve the improvement of antioxidant and anti-inflammatory status and inhibition on the activation of the NF-κB signaling. Hence, QC, a naturally occurring flavone with potent anti-psoriatic effects, has the potential for further development as a candidate for psoriasis treatment.

Chen H ，Lu C ，Liu H ，Wang M ，Zhao H ，Yan Y ，Han L ... -  《-》

Cimifugin ameliorates imiquimod-induced psoriasis by inhibiting oxidative stress and inflammation via NF-κB/MAPK pathway.

Cimifugin is an important component of chromones in the dry roots of Saposhikovia divaricata for treating inflammatory diseases. However, the possible effect of cimifugin in psoriasis needs further investigation. This current work was designed to evaluate the effects of cimifugin in psoriasis in vivo and in vitro, and unravel the underlying molecular mechanism. Here, we used imiquimod (IMQ) or tumor necrosis factor (TNF)-α to induce a psoriasis-like model in mice or keratinocytes. Obviously, the results showed that cimifugin reduced epidermal hyperplasia, psoriasis area severity index (PASI) scores, ear thickness and histological psoriasiform lesions in IMQ-induced mice. The decreased levels of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), and the accumulation of malondialdehyde (MDA) in skin tissues by IMQ were attenuated by cimifugin. Furthermore, it was observed that cimifugin effectively reversed IMQ-induced up-regulation of proinflammatory cytokines, including TNF-α, IL-6, IL-1β, IL-17A, and IL-22. Mechanically, we noticed that cimifugin inhibited IMQ-activated phosphorylation of NF-κB (IκB and p65) and MAPK (JNK, ERK, and p38) signaling pathways. Similar alterations for oxidative stress and inflammation parameters were also detected in TNF-α-treated HaCaT cells. In addition, cimifugin-induced down-regulation of ICAM-1 were observed in TNF-α-treated cells. Altogether, our findings suggest that cimifugin protects against oxidative stress and inflammation in psoriasis-like pathogenesis by inactivating NF-κB/MAPK signaling pathway, which may develop a novel and effective drug for the therapy of psoriasis.

Liu A ，Zhao W ，Zhang B ，Tu Y ，Wang Q ，Li J ... -  《-》