Psoriasis-like Inflammation Research Articles

Psoriasis-like Inflammation Induced in an Air-pouch Mouse Model.

The pathway of initiation of psoriasis comprises the differentiation and infiltration of T-helper 17 (Th17) cells into the skin, characterized by the production of interleukin 17A and 17F (IL-17A/IL-17F) among other cytokines, resulting in a downstream cascade of events. Due to the lack of simplicity in psoriasis models, we aimed to develop an easily and rapidly inducible mouse model for the IL-23/IL-17 pathway with quick readouts from a straightforward lavaging process and with detectable cytokine levels. We utilized the 6-day air-pouch mouse model, injected with a combination of anti-CD3, IL-23 and IL-1β. At 24, 48 and 72 h, intra-pouch secretion of IL-17A, IL-17F and C-X-C motif chemokine ligand 1 were measured. Skin biopsies were collected and immune cell infiltration evaluated, and intra-pouch immune cells were isolated and analyzed. The combination of anti-CD3, IL-23 with and without IL-1β significantly increased intra-pouch levels of IL-17A/IL-17F at 24 and 72 h, triggering a downstream production of C-X-C motif chemokine ligand 1. The cytokines were detectable even 72 h post-induction. T-cell receptor beta was down-regulated on CD4+ and CD8+ T-cells, indicating intra-pouch T-cell activation. Αnti-CD3 induced CD3+ cell migration into the subcutis and the lining tissue surrounding the cavity of the air pouch, where in the latter, a similar distribution pattern of Il17a mRNA-expressing cells was also observed. However, no Th17 cell differentiation nor changes in IL-17A+ granulocytes were observed. The induced air-pouch mouse model induced with a cocktail of anti-CD3, IL-23 with or without IL-1β is able to mirror the IL-23/IL-17 axis of psoriasis-like inflammation characterized by immune cell infiltration and cytokine secretion.

Natural product topical therapy in mitigating imiquimod-induced psoriasis-like skin inflammation-underscoring the anti-psoriatic potential of Nimbolide.

BACKGROUND:Psoriasis is a chronic inflammatory dermatological disorder having complex pathophysiology with autoimmune and genetic factors being the major players. Despite the availability of a gamut of therapeutic strategies, systemic toxicity, poor efficacy, and treatment tolerance due to genetic variability among patients remain the major challenges. This calls for effective intervention with the superior pharmacological profile. Nimbolide (NIM), a major limonoid is an active chemical constituent found in the leaves of the Indian Neem tre, Azadirachta indica. It has gained immense limelight in the past decades for the treatment of various diseases owing to its anti-proliferative, anti-inflammatory, and anti-cancer potentials.OBJECTIVE:The present study was centered around evaluating the anti-psoriatic effect of NIM in the experimental model of Imiquimod (IMQ)-induced psoriasis-like inflammation model.MATERIALS AND METHODS:Application of IMQ topically on the dorsum of Balb/c mice from day 0-6 prompted psoriasis-like inflammatory symptoms. Treatment groups included topical administration of NIM incorporated carbopol gel formulation and NIM free drug given through subcutaneous route. Protein expression studies such as immunohistochemistry, Western blotting, and ELISA were employed.RESULTS:It was clearly observed from our results that NIM significantly ameliorated the expression of inflammatory and proliferation mediators. Further, NIM in the treatment groups significantly improved classic Psoriasis Area Severity Index scoring when compared to IMQ administered group.CONCLUSION:It is noteworthy that NIM showed a predominant therapeutic effect as compared to other treatment group. To recapitulate, NIM has shown promising activity as an anti-psoriatic agent by remarkably ameliorating inflammation and associated proliferation.

OVOL1 Regulates Psoriasis-Like Skin Inflammation and Epidermal Hyperplasia

Psoriasis is a common inflammatory skin disease characterized by aberrant inflammation and epidermal hyperplasia. Molecular mechanisms that regulate psoriasis-like skin inflammation remain to be fully understood. Here, we show that the expression of Ovol1 (encoding ovo-like 1 transcription factor) is upregulated in psoriatic skin, and its deletion results in aggravated psoriasis-like skin symptoms following stimulation with imiquimod. Using bulk and single-cell RNA sequencing, we identify molecular changes in the epidermal, fibroblast, and immune cells of Ovol1-deficient skin that reflect an altered course of epidermal differentiation and enhanced inflammatory responses. Furthermore, we provide evidence for excessive full-length IL-1α signaling in the microenvironment of imiquimod-treated Ovol1-deficient skin that functionally contributes to immune cell infiltration and epidermal hyperplasia. Collectively, our study uncovers a protective role for OVOL1 in curtailing psoriasis-like inflammation and the associated skin pathology.

Assessment of anti-psoriatic activity of ethanolic extract of Justicia tranquebariensis Linn. on amelioration of IMQ-induced hyperkeratosis in Balb/C mice

Psoriasis characterized by abnormal keratinocyte hyper proliferation results in the thickening of the epidermis and the stratum corneum. Anti-psoriasis treatments available today are poorly efficient, having many side effects, making them unsuitable for therapeutic use. Hence, the search for safer and more effective drugs from natural resources is necessarily warranted. In the present study, the leaves of Justicia tranquebariensis Linn. have been evaluated for its anti-psoriatic activity to substantiate the traditional claim as an anti-psoriatic agent scientifically. Additionally, an EJTL ointment was formulated for the in vivo anti-psoriatic evaluation in Balb/c mice together with its histopathological study. The obtained results revealed the presence of primary phytochemicals, such as flavonoids and lignans in the ethanol extract of the leaves of J. tranquebariensis L. (EJTL). Furthermore, the UV-Visible and Fourier Transform Infrared Spectrums confirmed the existence of the relevant functional groups supports the presence of Isolariciresinol in the EJTL ethanol extract. In vivo evaluation of the EJTL ointment showed the remarkable anti-psoriatic activity in Balb/c mice with imiquimod (IMQ) induced psoriasis-like inflammation. The histopathological study results revealed significant improvement in skin lesion when compared to the positive control group. The anti-psoriatic activity further confirmed by observing the prominently decreased lymphocyte and keratinocyte infiltration in the dermis. A brief phytochemical characterization showed the presence of the active botanical ingredient, Isolariciresinol, assumed to have the anti-psoriatic property. Furthermore, the EJTL could be a potential drug for psoriasis either individually or synergistically with other herbals or anti-psoriatic agents.

Phospholipase C epsilon mediates cytokine cascade induced by acute disruption of epidermal permeability barrier in mice

Disruption of epidermal barrier is an important trigger in abnormal cutaneous inflammation. Phospholipase C epsilon (PLCε), a Ras/Rap1 effector, is essential for regulating cytokines production in different types of skin inflammation. Our previous studies have demonstrated that elevated expression of PLCε participates in the psoriasis-like inflammation in PLCε overexpressing transgenic mice model, while the reduction in PLCε expression attenuates inflammatory responses in either TPA- or DNFB-induced cutaneous inflammation. Here, we determined the role of PLCε in cutaneous inflammation induced by acute abrogation of epidermal permeability barrier. In comparison to wild type controls, PLCε KO mice exhibited reduced ear swelling and infiltration of granulocytes after tape-stripping. Moreover, expression levels of pro-inflammatory cytokines (IL-1α, IL-1β), chemokines (CXCL-1, CXCL-2, CCL20), and antimicrobial peptides (S100 proteins, MBD3) were lower in PLCε-deficient versus wild type mice. Likewise, expression levels of cytokines and chemokines were also lower in PLCε deficient keratinocytes and fibroblasts following IL-22 stimulation in vitro. Furthermore, knockdown of PLCε with its siRNA decreased expression of IL-1α, CCL20, and S100 proteins, and MBD3 in HEK cultures. Collectively, these results suggested that PLCε mediated cytokine cascade induced by acute barrier disruption. IL-22 is likely the upstream of PLCε-mediated cytokine cascade following acute barrier disruption.

Thymol activates TRPM8-mediated Ca2+ influx for its antipruritic effects and alleviates inflammatory response in Imiquimod-induced mice

Psoriasis is a highly prevalent chronic dermatitis, characterized by widespread skin inflammation and spontaneous itch. Given the adverse reactions and drug dependence of current treatment, new drugs for psoriasis therapy are urgently needed. This study aims to explore the anti-psoriatic effects of thymol in imiquimod (IMQ) induced mice, and elucidate the potential mechanisms for its therapeutic activities. Thymol reduced the scratching behavior in IMQ mice, and activated Ca2+ response in cervical DRG neurons via TRPM8 channel. Also, thymol alleviated psoriasis-like skin lesions, and attenuated the enhanced infiltration of dermal neutrophils, dendritic cells (DCs) and Th17 cells. In addition, it reversed the upregulated expression of pro-inflammatory cytokines in the skin (TNF-α, IL-22, IL-23, IL-17A, IL-17F, IL-17C, IL-6, IL-1β and IFN-γ) and serum (TNF-α, IL-6, IL-1β, IL-17A and IFN-γ). Our results indicated that thymol can effectively ameliorate pruritus and the symptoms of psoriasis-like inflammation induced by IMQ, which makes it a promising drug for the treatment of psoriasis.

MicroRNA-215-5p inhibits the proliferation of keratinocytes and alleviates psoriasis-like inflammation by negatively regulating DYRK1A and its downstream signalling pathways.

Psoriasis is a chronic inflammatory disease characterized by abnormal hyperproliferation and differentiation. The object of this study is to explore the role of microRNA-215-5p in psoriasis-like inflammation. The expression of miR-215-5p was found to be down-regulated in pro-inflammatory factor-stimulated HaCaT cells and imiquimod (IMQ)-treated skin tissues. Overexpression of miR-215-5p suppressed the proliferation and cell cycle progression of HaCaT cells. Further, miR-215-5p agomir alleviated the disease severity, pathological features and Ki67 positive cells in IMQ-treated mice. Luciferase assay confirmed that miR-215-5p could bind to the 3'UTR of DYRK1A. The in vitro and in vivo results showed that miR-215-5p negatively regulates DYRK1A, which further inhibited EGFR and its downstream signalling pathways, AKT and ERK. Collectively, our results provide evidence that overexpression of miR-215-5p inhibits the proliferation of HaCaT cells and alleviates psoriasis-like inflammation partly by DYRK1A mediated inhibition of the EGFR signalling pathway. miR-215-5p may serve as a novel small molecule for therapeutic intervention in psoriasis.

Multi-component clobetasol-loaded monolithic lipid-polymer hybrid nanoparticles ameliorate imiquimod-induced psoriasis-like skin inflammation in Swiss albino mice

Lipid-polymer hybrid nanoparticles (LPNs) exhibit several advantages over polymeric and non-polymeric systems in terms of improved drug loading, controlled release, stability, and cellular uptake. Herein we report a scalable and stable monolithic lipid-polymer hybrid nanoparticles (LPNs) consisting of a combination of lipids (solid and liquid) and an amphiphilic copolymer, mPEG-PLA. Clobetasol propionate, a topical corticosteroid, was encapsulated in the hydrophobic core of these LPNs that showed spherical shaped particles with a z-average size of 94.8 nm (PDI = 0.213) and encapsulation efficiency of 84.3%. These clobetasol loaded LPNs (CP/LPNs) were formulated into a topical hydrogel using carbopol 974P. CP/LPNs gel showed a sustained in vitro clobetasol release for 7 days with no burst release and 6 month stability at 2-8°C and room temperature. Further, CP/LPNs showed an improved cellular uptake with significant growth inhibition of HaCaT cells. In ex vivo studies, these LPNs penetrated into the viable epidermis and dermis region of the psoriatic skin with undetectable quantities leaching to the reservoir. Further, the topical application of CP/LPNs gel on Swiss albino mice with psoriasis-like inflammation showed negligible leaching of clobetasol into the systemic circulation. Efficacy assessment showed significantly improved PASI score, reduced skin damage and proliferation after treatment with CP/LPNs gel as compared to marketed product (Clobetamos™). Collectively, the enhanced cellular uptake, high skin penetration with increased skin retention, and improved efficacy demonstrate the potential of these LPNs for future clinical application.

Lycopene Inhibit IMQ-Induced Psoriasis-Like Inflammation by Inhibiting ICAM-1 Production in Mice.

Lycopene is the most abundant carotenoid in tomatoes, which has been identified to have the properties of anti-inflammation in addition to the capability to inhibit the expression of adhesion molecules. Intercellular adhesion molecules play a critical role in the pathogenesis of psoriasis. Here, we report that the topical use of a lycopene decreased imiquimod (IMQ)-induced psoriasis-like inflammatory responses, the progress of which was based on adhesion molecules. In vitro analysis showed that lycopene decreased keratinocyte and monocyte adhesion. Evidence suggests that intercellular adhesion molecule-1 (ICAM-1) is a main mediator of psoriasis pathogenesis. Therefore, it will be interesting to investigate the factors that contribute to the lycopene-mediated inhibition of ICAM-1 expression in psoriasis. We expect that lycopene will with potential value in the treatment of psoriasis.

315 Lipid accumulation in epidermal Langerhans cells correlate with aberrant immunofunctions in psoriasis-like inflammation

Psoriasis is a chronic, inflammatory, systemic disease characterized by abnormal lipid metabolism. Dendritic cells (DCs), an essential mediator in the pathogenesis of psoriasis, are recently discovered to be functionally regulated by intracellular lipid content. Being the sole DC subset within the epidermis, Langerhans cells (LCs) are potent regulators of immune surveillance and tolerance. Previous studies indicate a varying role of LCs in psoriasis with underpinning mechanism remains elusive. Here, we demonstrated aberrant maturation, enhanced phagocytosis and interleukin-23 (IL-23) over-secretion of LCs in imiquimod (IMQ)-induced psoriasis-like mouse skin. Remarkably, disease-associated LCs possessed an elevated level of neutral lipid content probably due to impaired autophagy of lipids other than altered lipid engulfment. Moreover, the inhibition of fatty acids synthesis, which resulted in a decrease in cellular neutral lipids, would significantly impair LC maturation and their production of IL-23. Further LC-MS analysis revealed a group of triglycerides (TG), diglycerides (DG), phosphatidylethanols (PEt) and phosphatidylcholines (PC) contributed to the increased neutral lipid level of LCs within IMQ-induced psoriasis-like skin. In accordance, low-input mRNA sequencing analysis uncovered the expressions of multiple genes involved in lipid metabolism, autophagy along with immunofunctions were correlatively dysregulated in murine disease-associated LCs. Single-cell RNA sequencing of psoriasis patients' LCs demonstrated an immune activation status of lesional LCs, which confirmed their pro-inflammatory role in the pathogenesis of psoriasis. Notably, hyperlipidemia does not directly influence LC homeostasis and immunofunction. In summary, lipid accumulation in epidermal Langerhans cells correlate with their aberrant immunofunctions in psoriasis-like inflammation.

223 Skin barrier, inflammation, and metabolism– connections through Ovol1/Ovol2

Skin barrier dysfunction contributes to inflammatory diseases such as psoriasis and atopic dermatitis, which can lead to systemic defects (e.g. atopic march). The cellular and molecular events that regulate barrier-induced inflammation and its connection to whole-body physiology remain to be fully understood. SNPs in human OVOL1, which encodes a transcriptional repressor, are associated with many skin inflammatory diseases. Germline deletion of Ovol1 leads to epidermal hyperproliferation and a transient delay in embryonic skin barrier acquisition. However, the function of Ovol1 and its homolog Ovol2 in adult skin homeostasis and inflammation is unknown. Here we show that skin epithelia-specific deletion of Ovol1 results in radically aggravated barrier disruption and psoriasis-like inflammation upon stimulation with imiquimod. Using ChIP-seq we found that Ovol1 protein in epidermal cells directly binds to the promoters of not only genes involved in controlling proliferation and differentiation (e.g. Id1) but also genes involved in inflammation (e.g. Cxcl1 and Nfkb2). We generated mice with both Ovol1 and Ovol2 inducibly deleted in adulthood specifically in epidermal cells and found the mice to rapidly develop skin barrier defects. Subsequently, they developed oversized paws with elongated and reddish toenails, and lower bodyweight and reduced fat deposits. Preliminary analysis using metabolic cages shows that these mice eat more and are metabolically more active than their control littermates. Additionally, they release more heat while maintaining a normal body temperature. Current experiments focus on characterizing potential inflammation in mutant mice and analyzing gene expression changes in skin and metabolic tissues such as brown adipose tissue of these mice. Our goal is to elucidate the mechanism by which Ovol1 and Ovol2 regulate skin barrier function and inflammation, and how cutaneous defects are linked to alterations in whole-body physiology and metabolism.

Electrophilic nitro-fatty acids suppress psoriasiform dermatitis through the inhibition of STAT3

Abstract Psoriasis is a systemic, immune-mediated disorder, characterized by chronic inflammatory skin and joint manifestations. Electrophilic nitro-fatty acids (NO2-FAs) have been reported to exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease. To study the therapeutic potential of NO2-FAs on psoriasis, we employed both acute and chronic murine experimental models of psoriasis. Our studies demonstrate that oral treatments of nitro-oleic acid (OA-NO2), prior to imiquimod (IMQ) or rIL-23 treatments, significantly inhibited the induction of psoriasis-like inflammation and inflammatory cytokine production in the skin. Moreover, utilizing transgenic murine models of psoriasis, we determined that OA-NO2 had both a preventative and therapeutic effect on psoriasiform inflammation. Mechanistic in vitro experiments demonstrated that OA-NO2 decreased IL-17A-induced IL-6 expression in normal human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Importantly, OA-NO2 also impaired signal transducers and activators of transcription 3 (STAT3) phosphorylation and translocation to the nucleus. Further mechanistic results indicated that OA-NO2 regulates STAT3 activation by post-translational modification of STAT3 via nitroalkylation. Overall, our results confirm the critical role of STAT3 in psoriasiform dermatitis and highlight the potential of NO2-FAs as therapeutic agents for the treatment of cutaneous inflammatory diseases, such as psoriasis.

Repression of miR-142–3p alleviates psoriasis-like inflammation by repressing proliferation and promoting apoptosis of keratinocytes via targeting Sema3A

Psoriasis is a multifactorial, recurring, and chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes. Evidence is rapidly accumulating for the role of microRNAs in psoriasis. The object of the study was to explore the functions and precise mechanism of miR-142–3p in human keratinocyte HaCaT cells in the presence of M5. Here, the results showed that miR-142–3p expression was heightened in HaCaT cells induced by M5. In addition, inhibition of miR-142–3p dramatically restricted cell proliferation and enhanced apoptosis in HaCaT cells exposed to M5, as exemplified by a decrease in the antiapoptotic Bcl-2 protein, concomitant with an increase in the proapoptotic proteins Bax. Moreover, depleting miR-142–3p effectively ameliorated M5-induced inflammation response, as reflected by the attenuation of multiple inflammatory factors. Importantly, Sema3A was identified as an authentic target of miR-142–3p, and indeed regulated by miR-142–3p. Mechanistically, silencing of Sema3A effectively abolished the anti-proliferative, apoptosis-promoting, and anti-inflammatory effects of miR-142–3p inhibition in keratinocytes. Taken together, these data elucidated that repression of miR-142–3p protect HaCaT cells against M5-induced hyper-proliferation and inflammatory injury by suppressing its target Sema3A, implying that the miR-142–3p/Sema3A axis may be a new target for preventing keratinocyte injury process. These findings provide a new and better understanding of the mediating role of miR-142–3p in psoriasis.

Therapeutic treatment with Ibrutinib attenuates imiquimod-induced psoriasis-like inflammation in mice through downregulation of oxidative and inflammatory mediators in neutrophils and dendritic cells

Psoriasis is clinically characterized by well-demarcated silvery plaques which may appear on the extremities, scalp, and sacral area. The multidimensional interactions among innate immune cells [neutrophils and dendritic cells (DCs)], adaptive immune cells and skin resident cells result in characteristic features of psoriatic inflammation such as acanthosis, hyperkeratosis, and parakeratosis. Tec family kinases are involved in the pathogenesis of several inflammatory diseases. One of them is Bruton’s tyrosine kinase (BTK) which is reported to carry out inflammatory and oxidative signaling in neutrophils and DCs. Effect of BTK inhibitor with regard to psoriatic inflammation has not been explored previously especially in a therapeutic setting. In the current investigation, effect of BTK inhibitor, Ibrutinib on oxidative/inflammatory signaling in dermal/splenic neutrophils [phosphorylated BTK (p-BTK), inducible nitric oxide synthase (iNOS), nitrotyrosine], CD11c + DCs (p-BTK, iNOS, nitrotyrosine, MCP-1, TNF-α) and enzymatic antioxidants [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR)] in imiquimod (IMQ)-induced psoriatic inflammation was evaluated using therapeutic mode. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in oxidative stress in neutrophils, and CD11c + DCs in skin/periphery. Therapeutic treatment with Ibrutinib caused attenuation of IMQ-induced oxidative stress in CD11c + DCs and neutrophils. Further there were dysregulations in antioxidants enzymes (SOD/GPx/GR) in the skin of IMQ-treated mice, which were corrected by Ibrutinib. In short, our study reveals that BTK signaling in neutrophils and CD11c + DCs upregulates oxidative stress which is concomitant with psoriatic inflammation in mice. Ibrutinib attenuates psoriasis inflammation through downregulation of oxidative stress in these innate immune cells.

Chrysin alleviates imiquimod-induced psoriasis-like skin inflammation and reduces the release of CCL20 and antimicrobial peptides

Psoriasis is a common non-contagious chronic inflammatory skin lesion, with frequent recurrence. It mainly occurs due to aberrant regulation of the immune system leading to abnormal proliferation of skin cells. However, the pathogenic mechanisms of psoriasis are not fully understood. Although most of the current therapies are mostly efficient, the side effects can result in therapy stop, which makes the effectiveness of treatment strategies limited. Therefore, it is urgent and necessary to develop novel therapeutics. Here, we investigated the efficacy of chrysin, a plant flavonoid, which we previously reported to possess strong antioxidant and anti-inflammatory effects, against psoriasis-like inflammation. Our results revealed that chrysin significantly attenuated imiquimod-induced psoriasis-like skin lesions in mice, and improved imiquimod-induced disruption of skin barrier. Moreover, the TNF-α, IL-17A, and IL-22-induced phosphorylation of MAPK and JAK-STAT pathways, and activation of the NF-κB pathway were also attenuated by chrysin pretreatment of epidermal keratinocytes. Most importantly, chrysin reduced TNF-α-, IL-17A-, and IL-22-induced CCL20 and antimicrobial peptide release from epidermal keratinocytes. Thus, our findings indicate that chrysin may have therapeutic potential against inflammatory skin diseases. Our study provides a basis for further investigating chrysin as a novel pharmacologic agent and contributes to the academic advancement in the field of Chinese herbal medicine.

Bruton’s tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton’s tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.

Psoriasis-Like Inflammation Induced Renal Dysfunction through the TLR/NF-κB Signal Pathway.

Pathological studies have shown an association between psoriasis and renal injury (RI), but the mechanism between RI and psoriasis was still unclear. This paper was designed to investigate the relationship and mechanism between psoriasis-like inflammation and renal injury in BALB/C mice. Mice were topically smeared imiquimod followed by various analyses in skin lesions, urine protein, kidney/serum inflammatory cytokines, kidney function, podocyte membrane proteins, and toll-like receptors/nuclear factor kappa-b (TLR/NF-κB) pathway-associated proteins. Meanwhile, lipopolysaccharide (LPS) and dexamethasone (DEX) were intraperitoneally injected to promote and inhibit inflammation accompanied by imiquimod to elaborate the relevance between inflammatory levels and RI. In the model group, the Psoriasis Area and Severity Index (PASI) scores of scaly and erythema obviously increased (p < 0.01), creatinine and blood urea nitrogen significantly increased (p < 0.01), the positive area of hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining in kidney increased (p < 0.01), malondialdehyde significantly increased with superoxide dismutase (SOD) decreased (p < 0.01), 24-hour urine protein increased and the expressions of podocin and CD2 associate protein (CD2AP) decreased (p < 0.01), and kidney/serum inflammatory factors (IL-17, IL-1β, IL-6, TNF-α, and IL-22) and TLR/NF-κB-related expression (TLR2, TLR4, MyD88, and NF-κBp65) all increased (p < 0.01). The RI was aggravated with the TLR/NF-κB related expression being upregulated by LPS (p < 0.05). On the contrary, the RI was alleviated by DEX (p < 0.05). Our data showed that psoriasis-like inflammation damaged the renal function via the TLR/NF-κB signal pathway. Inhibiting TLR/NF-κB-related protein expression may be effective for the treatment of RI caused by psoriasis.

Topical administration of nanocarrier miRNA-210 antisense ameliorates imiquimod-induced psoriasis-like dermatitis in mice.

Psoriasis is a chronic, recurrent inflammatory autoimmune skin disease. Although its etiology and pathogenesis are complex and multifarious, it has been proved to be closely related to dysregulation of immune cell function as well as keratinocyte proliferation/differentiation. Our previous study demonstrated that miRNA-210 (miR-210) plays an important role in the formation of skin lesions and immune imbalance in psoriasis. Here, we developed a biomimetic reconstituted high-density lipoprotein (rHDL) nanocarrier gel containing miR-210 antisense (NG-anti-miR-210) to investigate its effect on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice. We found that topical treatment with NG-anti-miR-210 significantly decreased the expression of miR-210 in both the skin lesions and splenic CD4+ T cells from IMQ-induced psoriasis-like mouse models and ameliorated the dermatitis in terms of the erythema, scales, acanthosis and dermal inflammatory cell infiltration in IMQ-induced mice. In addition, the proportion of T-helper (Th)1 and Th17 cells in dermal and splenic cells of IMQ-treated mice were decreased by application of NG-anti-miR-210, accompanied by decreased interleukin-17A and γ-interferon mRNA levels. Therefore, our data demonstrate that topical inhibition of miR-210 delivered by rHDL nanocarrier effectively alleviates the psoriasis-like inflammation in mice and provides a potentially effective topical drug for psoriasis.

STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation.

The transcription factors STAT3 and STAT4 are essential for lymphocyte differentiation and function. Interleukin (IL)-17 producing γδ T (γδT17) cells are innate lymphocytes important for anti-bacterial and inflammatory responses at barrier surfaces. Herein, we examine the role of STAT3 and STAT4 in regulating the homeostasis, activation, and pathogenicity of γδT17 cells. We show that STAT3 sustains γδT17 numbers in the skin but not in the lymph nodes, while STAT4 deficiency does not affect their homeostasis. Similarly, STAT3 but not STAT4 is essential for IL-23-induced IL-22 production by γδT17 cells. Concomitantly, mice lacking STAT3 expression in γδT17 cells develop significantly reduced psoriasis-like inflammation. STAT3-deficient γδT17 cells fail to expand and to upregulate IL-17A, IL-17F, and IL-22 in response to psoriatic stimuli. Although STAT4-deficient animals develop psoriasis-like disease, γδT17 cells in these mice are defective in IL-17F production. Collectively, our data demonstrate for the first time a critical role for STAT3 in orchestrating the homeostasis and pathogenicity of γδT17 cells and provide evidence for the requirement of STAT4 for optimal cytokine responses during inflammation.

331 Lymphatic flow blockade amplifies inflammation in imiquimod-induced psoriasis-like skin lesions

The lymphatic transport has important roles in coordinating local immune responses. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully understood. In this study, to further investigate the in vivo role of lymphatic system in skin inflammation, we induced psoriasis-like inflammation on mouse back skin or ear with topical application of imiquimod (IMQ), using k-cyclin transgenic (kCYC+/-) mice, which demonstrate severe lymphatic dysfunction. kCYC+/- mice showed severe clinical scores and enhanced ear swelling to IMQ treatment compared with wild-type littermates. Immunohistochemistry showed increased epidermal thickness. On the other hand, mRNA expression levels of inflammatory cytokines including IFN-γ, TNF-α, and IL-17A, in IMQ-treated skin were comparable between kCYC+/- mice and wild-type mice. Interestingly, western blot analyses revealed that protein expression levels of IFN-γ, TNF-α, IL-17A, IL-22, and IL-23 were significantly upregulated in IMQ-treated skin of kCYC+/- mice compared to wild-type mice. Consistently, phosphorylation of STAT3, which can be induced by IL-17 and IL-22 and associated with epidermal hyperplasia, was also augmented in epidermal keratinocytes in IMQ-treated skin of kCYC+/- mice. These results suggest that lymphatic dysfunction in kCYC+/- mice caused accumulation of inflammatory cytokine proteins without upregulation of mRNA expressions, resulting in exacerbation of IMQ-induced psoriasis-like skin inflammation. The findings add insight into the clinical problem of inflammatory dermatitis that commonly occurs in humans with peripheral edema of the lower legs.