Psoriasiform Skin Inflammation Research Articles

MiR-378a regulates keratinocyte responsiveness to interleukin-17A in psoriasis.

BackgroundPsoriasis is an immune‐mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)‐17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes.ObjectivesTo explore the role of miR‐378a in psoriasis.MethodsKeratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR‐378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR‐378a was studied using primary human keratinocytes. The expression of miR‐378a was modulated by synthetic mimics, and nuclear factor kappa B (NF‐κB) activity and transcriptomic changes were studied. Synthetic miR‐378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod.ResultsWe show that miR‐378a is induced by IL‐17A in keratinocytes through NF‐κB, C/EBP‐β and IκBζ and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR‐378a resulted in the nuclear translocation of p65 and enhanced NF‐κB‐driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR‐378a potentiated the effect of IL‐17A on NF‐κB nuclear translocation and downstream activation of the NF‐κB pathway. Finally, injection of miR‐378a into mouse skin augmented psoriasis‐like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR‐378a acts as a suppressor of NFKBIA/IκBζ, an important negative regulator of the NF‐κB pathway in keratinocytes.ConclusionsCollectively, our findings identify miR‐378a as an amplifier of IL‐17A‐induced NF‐κB signalling in keratinocytes and suggest that increased miR‐378a levels contribute to the amplification of IL‐17A‐driven skin inflammation in psoriasis.

Dietary olive oil intake aggravates psoriatic skin inflammation in mice via Nrf2 activation and polyunsaturated fatty acid imbalance

Psoriasis is a chronic inflammatory skin disease, which does not have effective treatment options. However, olive oil has been suggested as an alternative to treat psoriasis, but no study has evaluated the mechanisms involved in the effects of olive oil on psoriasis. Thus, the current study investigated whether olive oil could ameliorate psoriasiform skin inflammation. To test this, mice received topical application of imiquimod to induce inflammation and were treated orally with olive oil. Human immortalized keratinocytes were also treated with imiquimod and olive oil. Epidermal thickness and keratinocyte proliferation were increased in imiquimod-induced lesions of olive-oil-treated animals. In both in vitro and in vivo studies, protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were elevated following imiquimod and olive oil administration. Inhibition of Nrf2 abolished the increased proliferation of keratinocytes treated with imiquimod and olive oil, demonstrating the role of Nrf2 in olive oil-mediated exacerbation of psoriasiform skin inflammation. In addition, lower levels of linoleic acid and higher levels of oleic acid were observed in imiquimod- and olive-oil-treated animals, which may also contribute to the adverse effects of olive oil on psoriasis. In conclusion, dietary intake of olive oil aggravates the symptoms of psoriatic skin lesions through the overexpression of Nrf2 and an imbalance in oleic and linoleic acids levels, suggesting that a diet rich in olive oil may have significant negative effects on psoriasis.

Adiponectin-derived pentapeptide ameliorates psoriasiform skin inflammation by suppressing IL-17 production in γδT cells

BackgroundPsoriasis is a common immunologic chronic skin disease that affects at least 100 million individuals worldwide. Adiponectin is associated with psoriasis and suppresses psoriasiform inflammation. Recently, a small-sized transdermally deliverable 5-mer peptide (GLYYF; P5) was discovered as a potential adiponectin receptor 1 agonist. ObjectivesTo confirm reduction in adiponectin protein level in the human skin and investigate whether functional adiponectin replenishment by topical P5 application improves psoriasiform skin inflammation. MethodsAdiponectin protein expression in the skin of individuals with psoriasis and normal skin was examined by immunofluorescence staining. Imiquimod-induced psoriasis-like skin inflammation was induced in wild-type (WT) and adiponectin-deficient (Adipoq−/−) mice. Vehicle and P5 were topically applied to the back skin and ears of mice. Histological study, reverse-transcription quantitative polymerase chain reaction, multiplex-bead array assay, and flow cytometric analysis were performed. ResultsAdiponectin protein expression was downregulated both in the epidermis and dermis of psoriatic lesions as compared to that in the normal skin. Topically applied P5 attenuated the severity of imiquimod-induced psoriatic dermatitis in both WT and Adipoq−/− mice by decreasing the expression of psoriasis-related cytokines (Il17a, Il1b, Il6, and Tnfa). P5 application significantly reduced the proportion of interleukin-17A–producing γδT cells. ConclusionTransdermally deliverable adiponectin receptor 1 agonist, P5, can be a potential peptide drug to manage psoriasis by mediating the anti-psoriatic effect of adiponectin

Transcutaneous delivery of mung bean-derived nanoparticles for amelioration of psoriasis-like skin inflammation.

Psoriasis is a complex autoimmune disease that is closely associated with the disorganized pro-inflammatory polarization of macrophages and the activation of inflammatory signalling pathways. Nanoparticles (NPs) have shown their potential in immune response regulation and the related treatment of inflammatory diseases. Herein, we report the modulation of the skin immune system for amelioration of psoriasis-like skin inflammation using mung bean-derived NPs (MBNs), which exhibit high antioxidant activity to reduce reactive oxygen species (ROS) and modulate the immune microenvironment. For imiquimod (IMQ)-stimulated psoriasis-like skin, topical administration of MBNs can achieve the homeostasis of polarized macrophages and antagonize the activation of the nuclear factor kappa B (NF-κB) signalling pathway, which result in the alleviation of skin inflammation. The transcutaneous delivery of MBNs provides a promising approach for the treatment of psoriasis and other inflammatory skin diseases.

Salubrinal protects against inflammatory response in macrophage and attenuates psoriasiform skin inflammation by antagonizing NF-κB signaling pathway

Psoriasiform skin inflammation is the common chronic skin inflammatory disease with no effective clinical therapy. Salubrinal is a multifunctional molecule playing a protective role in several conditions. Recently, studies have reported that Salubrinal is a potential therapeutic agent for inflammatory diseases. However, the protective role of Salubrinal in psoriasis-like skin inflammation remains unknown. In this article, imiquimod (IMQ)-induced psoriasis models were established in wild-type mice to explore the role of Salubrinal in the development of psoriasis. As a result, the IMQ-induced mouse models exhibited typical skin inflammation, which was alleviated by the administration of Salubrinal. Furthermore, RAW264.7 macrophage was stimulated with Lipopolysaccharide(LPS) in the presence or absence of Salubrinal. LPS stimulation elevated the expression of various inflammatory biomarkers, while the administration of Salubrinal abolished the function of LPS in RAW264.7 macrophages. In addition, the activation of the nuclear factor-kappa B (NF-κB) signaling pathway in both the LPS-stimulated RAW264.7 macrophage and psoriasis mouse models was antagonized by the administration of Salubrinal. Collectively, Salubrinal might be considered as a promising therapeutic agent for psoriasis-like skin inflammation.

Keratinocyte-intrinsic BCL10/MALT1 activity initiates and amplifies psoriasiform skin inflammation.

Psoriasis is a chronic inflammatory skin disease arising from poorly defined pathological cross-talk between keratinocytes and the immune system. BCL10 (B cell lymphoma/leukemia 10) and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) are ubiquitously expressed inflammatory signaling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. We report that although keratinocyte-intrinsic BCL10/MALT1 deletions completely rescue inflammatory skin pathology triggered by germline Card14 gain-of-function mutation in mice, the BCL10/MALT1 signalosome is unexpectedly not involved in the CARD14-dependent interleukin-17 receptor (IL-17R) proximal pathway. Instead, it plays a more pleiotropic role by amplifying keratinocyte responses to a series of inflammatory cytokines, including IL-17A, IL-1β, and TNF. Moreover, selective keratinocyte-intrinsic activation of BCL10/MALT1 signaling with an artificial engager molecule is sufficient to initiate lymphocyte-mediated psoriasiform skin inflammation, and aberrant BCL10/MALT1 activity is frequently detected in the skin of human sporadic psoriasis. Together, these results establish that BCL10/MALT1 signalosomes can act as initiators and crucial amplifiers of psoriatic skin inflammation and indicate a critical function for this complex in sporadic psoriasis.

Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease that affects approximately 2–3% of the population worldwide. Although there is increasing evidence regarding the essential roles of the interleukin (IL)-23/IL-17 axis and dendritic cell (DC)-T cell crosstalk in the development of skin inflammation, the contributions of mitochondrial function to psoriasis are unclear. In a mouse model of imiquimod (IMQ)-induced psoriasiform skin inflammation, we found that hematopoietic cell-specific genetic deletion of p32/C1qbp, a regulator of mitochondrial protein synthesis and metabolism, protects mice from IMQ-induced psoriatic inflammation. Additionally, we demonstrate that p32/C1qbp is an important regulator of IMQ-induced DC activation, both in vivo and in vitro. We also found that p32/C1qbp-deficient DCs exhibited impaired production of IL-1β, IL-23, and mitochondrial reactive oxygen species (mtROS) after IMQ stimulation. Because the inhibition of mtROS suppressed IMQ-induced DC activation and psoriatic inflammation, we presume that p32/C1qbp and mtROS can serve as therapeutic targets in psoriasis.

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.

Effect of Topical Tadalafil Gel in Imiquimod-induced Psoriasiform Skin Inflammation in Mice

Effect of Topical Tadalafil Gel in Imiquimod-induced Psoriasiform Skin Inflammation in Mice

Skin-Homing Regulatory B Cells Required for Suppression of Cutaneous Inflammation

Pro and anti-inflammatory B-cell subsets that localize to unperturbed and inflamed skin are newly emerging components of the skin immune system. To test the relevance of regulatory B cells (Bregs) in the suppression of cutaneous inflammation, we asked whether impaired migration of these cells into the skin exacerbates skin inflammation. Using a mouse model with a B-cell‒specific tamoxifen-inducible deletion of α4β1 integrin, we demonstrate that selective disruption of α4β1-integrin expression in B cells significantly decreases IL-10+ Bregs in inflamed skin, whereas it does not affect their counterparts in lymphoid tissues. Impaired skin homing and reduced cutaneous accumulation of IL-10+ Bregs lead to a significant increase in clinical and histopathological parameters of inflammation in both psoriasiform skin inflammation and cutaneous delayed contact hypersensitivity. Thus, our data show a crucial function of skin-homing IL-10+ Bregs in the suppression of skin inflammation, supporting the notion that Bregs are critical players in the cutaneous environment during inflammatory skin diseases.

TLR2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation through Decrease in Regulatory T Cells and Impaired IL-10 Production.

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.

Inhibiting Protein Kinase Activity of Pyruvate Kinase M2 by SIRT2 Deacetylase Attenuates Psoriasis

Signal transducer and activator of transcription 3 (STAT3) is crucial for the pathogenesis of psoriasis. Studies describe pleiotropic roles for a glycolytic enzyme pyruvate kinase M2 (PKM2) as a nuclear kinase of STAT3. However, little is known about the function of PKM2 in T helper type 17 cells in association with STAT3. In this study, we investigated whether and how SIRT2 deacetylase regulated the protein kinase function of PKM2 in T helper type 17 cell‒mediated inflammatory responses in psoriasis. Sirt2 knockout mice and wild-type littermates had psoriatic dermatitis induced by topical treatment of imiquimod or intradermal injection of recombinant IL-23. An initial downregulation of SIRT2 and an increase in PKM2 acetylation and STAT3 phosphorylation were observed in psoriasiform lesions of mice. SIRT2 directly interacted with and deacetylated PKM2 to suppress STAT3 phosphorylation. Consequently, psoriasiform skin inflammation was aggravated in Sirt2 knockout mice. Conversely, genetic re-expression of Sirt2 or pharmacological blockade of PKM2 decreased the disease severity. Flow cytometric analysis of skin tissues of Sirt2 knockout mice showed enhanced infiltration of T helper type 17 cells. Exvivo experiments showed that SIRT2 deficiency accelerated T helper type 17 cell differentiation with the concomitant production of IL-17A and IL-22. The results suggest SIRT2-mediated PKM2 deacetylation as an effective option for psoriasis therapy.

Immunity to commensal skin fungi promotes psoriasiform skin inflammation

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.

C5a/C5aR1 mediates IMQ-induced psoriasiform skin inflammation by promoting IL-17A production from γδ-T cells.

Psoriasis is a chronic relapsing inflammatory skin disease, affecting up to 3% of the global population. Accumulating evidence suggests that the complement system is involved in its pathogenesis. Our previous study revealed that the C5a/C5aR1 pathway is crucial for disease development. However, the underlying mechanisms remain largely unknown. To explore potential mechanisms, psoriatic skin lesions and histological changes were assessed following imiquimod (IMQ) cream treatment. Inflammatory cytokine expression was tested by real-time RT-PCR. Immunohistochemistry and flow cytometry were used to identify inflammatory cell infiltration and interleukin (IL-17A) IL-17A expression. A C5aR1 antagonist (C5aR1a) and PI3K inhibitor (wortmannin) were used for blocking experiments (both in vivo and in vitro) to explore the mechanism. C5a/C5aR1-pathway inhibition significantly attenuated psoriasis-like skin lesions with decreased epidermal hyperplasia, downregulated type 17-related inflammatory gene expression, and reduced IL-17A-producing γδ-T cell responses. Mechanistically, C5a/C5aR1 promoted the latter phenotype via PI3K-Akt signaling. Consistently, C5aR1 deficiency clearly ameliorated IMQ-induced chronic psoriasiform dermatitis, with a significant decrease in IL-17A expression. Finally, blocking C5aR1 signaling further decreased psoriasiform skin inflammation in IL-17-deficient mice. Results suggest that C5a/C5aR1 mediates experimental psoriasis and skin inflammation by upregulating IL-17A expression from γδ-T cells. Blocking C5a/C5aR1/IL-17A axis is expected to be a promising strategy for psoriasis treatment.

157 IL-10+ regulatory B cell migration into inflamed skin limits cutaneous inflammation

To maintain skin homeostasis several types of leukocytes exist in or are recruited into the skin. While most of these leukocytes are well characterized, the roles of skin-associated B cells remain largely unknown. Our lab previously demonstrated that a subset of IL-10+ regulatory B cells preferentially migrates into the inflamed skin of mice, a process that required α4β1 integrin. Thus, we hypothesized that B regulatory cells suppress skin inflammation and that impaired migration of these cells into the skin exacerbates skin inflammation. To test this hypothesis, we used two mouse models of skin inflammation: (i) IL-17-dominated psoriasiform skin inflammation induced by imiquimod (IMQ) cream and (ii) IFN-γ-mediated cutaneous delayed contact hypersensitivity elicited by dinitrofluorobenzene (DNFB). Furthermore, we employed a mouse model with a B cell-specific tamoxifen-inducible deletion of α4-integrin (Itga4). Here, we found that inducing the deletion of Itga4 in B cells led to a significant decreased in skin-associated IL-10+ B cells in inflamed skin and included both conventional B2 (CD19+B220highCD43-) and innate-like B1 (CD19+B220-/lowCD43+) cells. The decrease accumulation of IL-10+ regulatory B cells was associated with a significant increase in the clinical and histopathological parameters of skin inflammation in both skin inflammation models. Thus, our data show a crucial function of skin-homing IL-10+ regulatory B cells in the suppression of IL-17- and IFN-γ-dominated skin inflammation; supporting the notion that B regulatory cells are critical players in the cutaneous environment during inflammatory skin diseases.

Topical application of endothelin receptor A antagonist attenuates imiquimod-induced psoriasiform skin inflammation

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamine-independent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ) -induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.

Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice.

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

Sensory Neuron–Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice

Psoriasis is an inflammatory skin disease associated with itch, which is a troublesome symptom with a few therapeutic options. TRPC4 is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in Trpc4-knockout mice and ML204-treated mice. We have also shown that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after the repeated application of imiquimod, which is a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed imiquimod-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefits.

Effects of tumor necrosis factor-like ligand 1A (TL1A) on imiquimod-induced psoriasiform skin inflammation in mice.

TL1A, as a master regulatory cytokine, plays a key role in the development of diverse T-cell-mediated inflammatory and autoimmune diseases. Our study is to further understand the roles of TL1A in the pathogenic mechanism of psoriasis and to find a possible new therapeutic strategy in the treatment of psoriasis. The direct effects of TL1A injection in mice skin and the therapeutic effects of TL1A blockade in imiquimod (IMQ)-induced psoriasis-like mouse model were researched in this study. First, we found that the expressions of TL1A in IMQ-treated lesions were significantly higher than Vaseline control group. And then, the results showed that TL1A injection exacerbated the psoriasiform phenotype on IMQ-treated skin (including clinical score, epidermal thickness changes, and Baker score) by increasing the number of T cells, neutrophils, and DCs, and upregulating the mRNA expression of IFN-γ and IL-17. However, anti-TL1A mAb can alleviate psoriasis-like lesions in clinical and effectively improved the histopathologic changes in IMQ-induced psoriasis-like mice after treatment. Moreover, anti-TL1A mAb also reduced the number of infiltrated CD3+ T cells, MPO+ neutrophils, and CD11c+ DCs in psoriasis-like lesions, and obviously decreased the expression of IFN-γ and IL-17 in psoriasis-like lesions. Data suggested that TL1A might be involved in the pathogenesis of psoriasis, and targeting TL1A by anti-TL1A mAb might provide a solid foundation and novel therapeutic sight in the treatment of psoriasis.

Liraglutide improved inflammation via mediating IL-23/Th-17 pathway in obese diabetic mice with psoriasiform skin

Objectives The purpose of this study was to investigate the effect of liraglutide on obesity diabetic mice with psoriasiform skin inflammation. Methods Wild-type mice and db/db mice were randomly divided into five groups (n = 6): including the control group which received Vaseline, the imiquimod (IMQ)-induction group and the liraglutide-treatment group. The advanced treatment with liraglutide (0.3 mg/kg/d) for 4 weeks before IMQ induced psoriatic skin inflammation in the db/db + IMQ + Lira group. Basic parameters of diabetes, PASI, histopathology of skin, the expression of IL-17A, IL-23, IL-22, and TNF-α in the skin of back were measured. Results After IMQ induction, the psoriatic skin inflammation and pathological changes in the db/db + IMQ group were more serious than those in the WT + IMQ group. The glucose metabolism and insulin resistance of in the db/db + IMQ + Lira group were significantly improved, Psoriasis Area and Severity Index (PASI) was significantly reduced, and the protein and mRNA expressions of IL-23, IL-17, IL-22, and TNF-α in the back skin tissues were decreased. Conclusions Liraglutide can improve psoriasis skin lesions of obese diabetic mice, and the mechanism may be related to the inhibition of the expression of IL-23, IL-17, IL-22, and TNF-α through the IL-23/Th-17 pathway.