Psoriasiform Skin Inflammation Research Articles

Effects of topical isoxsuprine ointment on imiquimod-induced psoriasiform skin inflammation in mice.

This study assesses the potential positive impact of a 0.05% isoxsuprine ointment on psoriasiform skin inflammation generated by imiquimod in mouse models. Thirty-two male albino mice were allocated into four groups: the control group (which received topical emollients twice daily for 16days), the induction group (which received imiquimod cream (5%) for 8days, twice daily followed by petrolatum gel (15%) for another 8days), and the other two groups, which received imiquimod cream (5%) for 8days followed by either clobetasol ointment (0.05%) or isoxsuprine ointment (0.05%) twice daily for an additional 8days. At the end of the experiment, mice were sacrificed by ethical standards, and levels of TNF-α, IL-6, IL-17A, IL-23, and VEGF were measured; PASI and Backer's score were examined, in addition to the histopathology of skin tissue. Each clobetasol and isoxsuprine group displayed a significant reduction in tissue homogenate levels of TNF-α, IL-6, IL-17A, IL-23, and VEGF, besides increments in IL-10 compared to the induction group. Some markers (IL-17A, IL23, and VEGF) showed no significant difference between clobetasol and the isoxsuprine group. In contrast, the other markers (TNF-α, IL6, and IL10) showed significant differences between clobetasol and isoxsuprine groups. Isoxsuprine ointment showed comparable efficacy to clobetasol ointment in treating imiquimod-induced psoriasiform skin inflammation in mice models, probably due to its possible effect of anti-inflammatory and immunomodulatory activities.

Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment

Psoriasis is a multifactorial, chronic inflammatory skin disease with unresolved questions on its primary events. Iron overload has been described in the epidermis of psoriasis patients, but its relevance remains unknown. We found that the key iron regulatory hormone hepcidin was highly expressed in the epidermis of psoriasis patients, especially the pustular variants resistant to treatments. In a murine model of acute skin inflammation, keratinocyte-derived hepcidin was required for iron retention in keratinocytes, leading to hyperproliferation of the epidermal layer and neutrophil recruitment, two main features of psoriatic skin lesions. Keratinocytes overexpressing hepcidin were sufficient to elicit these psoriasiform features in a transgenic mouse model. Furthermore, transcriptome analysis of these keratinocytes revealed canonical pathways found in human psoriasis, pointing to a causal role for hepcidin in the pathogenesis of the disease. Altogether, our data suggest that hepcidin could be an actionable target for skin psoriasis treatment, in addition to current therapeutics, or targeted as maintenance therapy during remission to prevent recurrence.

NETs contribute to psoriasiform skin inflammation: A novel therapeutic approach targeting IL-36 cytokines by a small molecule tetrahydroxystilbene glucoside

BackgroundPsoriasis, a chronic immune-mediated skin disease with pathological features such as aberrant differentiation of keratinocytes, dermal-epidermal inflammation, and angiogenesis. 2,3,5,4′-Tetrahydroxy stilbene 2-Ο-β-d-glucoside (2354Glu) is a natural small molecule polyhydrostilbenes isolated from Polygonum multiglorum Thunb. The regulation of IL-36 subfamily has led to new pharmacologic strategies to reverse psoriasiform dermatitis. PurposeHere we investigated the therapeutic potential of 2354Glu and elucidated the underlying mechanism in psoriasis. MethodsThe effects of 2354Glu on IL-36 signaling were assessed by psoriasiform in vivo, in vitro and ex vivo model. The in vivo mice model of psoriasis-like skin inflammation was established by applying imiquimod (IMQ), and the in vitro and ex vitro models were established by stimulating mouse primary keratinocyte, human keratinocytes cells (HaCaT) and ex vivo skin tissue isolated from the mice back with Polyinosine-polycytidylic acid (Poly(I:C)), IMQ, IL-36γ and Lipopolysaccharide (LPS) respectively. Moreover, NETs formation was inhibited by Cl-amidine to evaluate the effect of NETs in psoriatic mouse model. The effects of 2354Glu on skin inflammation were assessed by western blot, H&E, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay and real-time quantitative PCR. ResultsIn Poly(I:C)-stimulated keratinocytes, the secretion of IL-36 was inhibited after treatment with 2354Glu, similar to the effects of TLR3, P2X7R and caspase-1 inhibitors. In aldara (imiquimod)-induced mice, 2354Glu (100 and 25 mg/kg) improved immune cell infiltration and hyperkeratosis in psoriasis by directly targeting IL-36 in keratinocytes through P2X7R-caspase-1. When treatment with 2354Glu (25 mg/kg) was insufficient to inhibit IL-36γ, NETs reduced pathological features and IL-36 signaling by interacting with keratinocytes to combat psoriasis like inflammation. Conclusion: These results indicated that NETs had a beneficial effect on psoriasiform dermatitis. 2354Glu alleviates psoriasis by directly targeting IL-36/P2X7R axis and NET formation, providing a potential candidate for the treatment of psoriasis.

Are periodontitis and psoriasis associated? A pre-clinical murine model.

To investigate the bidirectional influence between periodontitis and psoriasis, using the respective experimental models of ligature- and imiquimod-induced diseases on murine models. Thirty-two C57/BL6J mice were randomly allocated to four experimental groups: control (P- Pso-), ligature-induced periodontitis (P+ Pso-), imiquimod-induced psoriasis (P- Pso+) and periodontitis and psoriasis (P+ Pso+). Samples (maxilla, dorsal skin and blood) were harvested immediately after death. Measures of periodontitis (distance between the cemento-enamel junction and alveolar bone crest [CEJ-ABC] and the number of osteoclasts) and psoriasis (epidermal thickness and infiltrate cell [/0.03mm2]) severity as well as systemic inflammation (IL-6, IL-17A, TNF-α) were collected. The P+ Pso+ group exhibited the most severe experimental periodontitis and psoriasis, with the highest values of CEJ-ABC, number of osteoclasts, epidermal thickness and infiltrate cells in the dorsal skin, as well as the highest blood cytokine concentration. The P+ Pso- group presented with higher cell infiltrate (/0.03mm2) compared to the control group (p <.05), while the P- Pso+ group showed substantially higher alveolar bone loss (CEJ-ABC) than the control group (p <.05). Experimental periodontitis may initiate and maintain psoriasiform skin inflammation and, vice versa, experimental psoriasis may contribute to the onset of periodontitis. In a combined model of the diseases, we propose a bidirectional association between periodontitis and psoriasis via systemic inflammation.

Abstract 1405: Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy

Abstract Interleukin-22 (IL-22) is an inflammatory cytokine involved in the pathology of autoimmune diseases such as psoriasis, atopic dermatitis, and ulcerative colitis. IL-22 has also been shown to promote epithelial cell proliferation, stemness and tumorigenesis in cancer, and is associated with a more aggressive phenotype in a variety of cancers including inflammatory colon cancer models. IL-22 plays a central role in this pathogenic process by driving activation of STAT3 and other signaling cascades. Recent studies demonstrated that neutralization of IL-22 reduced dysplasia and tumor development in preclinical models. However, there has not been a clear application for anti-IL-22 therapy for cancer and autoimmune diseases, likely due to identifying the right disease indication and their low potency and efficacy. Thus, there remains an opportunity to explore the potential of more potent anti-IL-22 therapeutics. We have developed humanized anti-IL-22 antibodies with high affinities to human, cynomolgus and mouse IL-22 using BioAtla’s proprietary antibody discovery and engineering platforms. In vitro data demonstrated that our anti-IL-22 antibodies inhibited IL-22-induced p-STAT3 activities. In addition, our antibodies showed a 10-fold increased binding activity to human IL-22 compared to Fezakinumab, which was previously developed by Pfizer for the treatment of autoimmune diseases. To test the functions of our antibodies in vivo, we established an inflammation-driven sporadic colitis-associated colorectal (CAC) cancer mouse model. Our humanized anti-IL-22 antibody, a potent, species cross-reactive anti-IL-22 blocking antibody, significantly reduced tumor progression in CAC model. These data suggest that targeting IL-22 reduces tumor occurrence by reducing inflammation-induced tumorigenesis. In addition, we evaluated our anti-IL22 antibodies in an imiquimod-induced psoriasiform skin inflammation mouse model. The mice treated with anti-IL22 antibodies had significantly reduced skin lesions compared to isotype antibody-treated mice. Q-PCR analysis of the mouse skin demonstrated that treatment with our anti-IL-22 antibody led to significantly decreased RNA levels of the imiquimod-induced inflammatory marker CXCL3. In conclusion, the development of a potent, species cross-reactive anti-IL-22 antibody using BioAtla’s antibody discovery and engineering platforms addresses the past challenges of anti-IL-22 therapeutics and allows for translational studies in relevant animal efficacy and safety models. Citation Format: Jian Chen, Cathy Chang, Gerhard Frey, Haizhen Liu, Jing Wang, William J. Boyle, Jay M. Short. Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1405.

ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation, as ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK, as it physically binds to and assists in degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasiss therapy.

Methotrexate and electrostimulation cooperate to alleviate the relapse of psoriasiform skin inflammation by suppressing memory T cells

Methotrexate (MTX) is an immunosuppressant used to treat autoimmune diseases, including psoriasis. However, like other immunosuppressants, MTX alone does not prevent their recurrence. Electrostimulation (ES) has been utilized to treat some inflammatory disorders without any major side-effect. But it remains unknown if ES alone, or together with MTX, ameliorates autoimmune disease relapse: a sticky medical problem. In particular, the mechanisms underlying ES action remain unclear. The objective of this study was to determine an impact of ES and/or MTX on psoriasis relapse and their potential cooperation. We found that regional ES, but not MTX, ameliorated psoriasiform skin inflammation recurrence. Interestingly, treatment with both MTX and ES further prevented psoriasis recurrence compared to ES alone. Moreover, ES downregulated potassium channel Kv1.3 on T-cells and reduced CD4+/CD8+ effector memory (TEM) and CD8+ skin-resident memory T (TRM) cells, while ES plus MTX further decreased CD8+ TEM/TRM cells compared to ES alone. However, ES failed to further attenuate psoriasis recurrence or suppress T cell memory in Kv1.3-deficient mice, whereas lack of Kv1.3 itself ameliorated psoriasis relapse by shrinking T cell memory pool. Importantly, ES moderately inhibited T-cell proliferation in vitro. ES also reduced human CD8+ TRM cells and attenuated human skin lesions in humanized mice grafted with lesional skin from patients with recurrent psoriasis, with an enhanced efficacy in mice treated with both ES and MTX. Thus, ES and MTX cooperated to prevent psoriasis relapse by reducing T-cell memory via targeting potassium channel Kv1.3. Our studies may be implicated for treating human psoriasis.

086 Chd4 epigenetically regulates RORγt-dependent IL-17A production in γδT cells to promote psoriasiform skin inflammation

086 Chd4 epigenetically regulates RORγt-dependent IL-17A production in γδT cells to promote psoriasiform skin inflammation

Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis

Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc+ papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.

Tumor-Derived PD-L1+ Exosomes with Natural Inflammation Tropism for Psoriasis-Targeted Treatment.

Psoriasis is a chronic inflammatory disease whose etiology is directly related to the dysregulation of cutaneous immune homeostasis. However, how to finely modulate the skin immune microenvironment to restore homeostasis remains an important challenge. Inspired by the natural attribute of tumor exosomes in the immune escape, the tumor-derived exosomes as an active targeting nanoplatform for the effective treatment of inflammatory skin disorder were first reported. As keratinocytes and immune cells express high PD-1 during the onset of psoriasiform skin inflammation, the PD-L1-positive exosomes derived from melanoma cells carrying pristimerin with extremely anti-inflammatory potential were yielded to treat psoriasis. The PD-L1+ exosomes carrying pristimerin were characterized, and the cellular uptake was performed to evaluate the PD-1 target capability. The anti-inflammatory action of PD-L1+ exosomes carrying pristimerin was observed in both in vitro and in vivo models of psoriasis. Our exosomes substantially increased pristimerin uptake with CD4+ T cells and keratinocytes, significantly inhibited the proliferation of Th17 cells, and promoted Treg differentiation in a psoriasis-like model. Obviously, PD-L1+ exosomes carrying pristimerin significantly and safely reversed imiquimod (IMQ)-induced psoriasis in mice, indicated by reducing epidermal thickness, decreasing plaque formation, and suppressed excessive inflammatory response, due to its dual targeting of both CD4+ T cells and keratinocytes gathering around the lesion. The inflammatory cell infiltration and pro-inflammatory cytokine production in psoriasis were suppressed by our engineered exosomes. Besides, PD-L1+ exosomes carrying pristimerin treatment alleviated ferroptosis-related changes in psoriatic skin, thereby dampening excessive inflammation and, in turn, decreasing the abnormal proliferation of keratinocytes in psoriatic lesions. This study demonstrates that our engineered exosomes can not only act as a treat-to-target strategy for psoriasis treatment but also provide insight in clinical application of inflammatory disorders.

Abstract 6335: Developing anti-IL-22 therapeutics for inflammation and cancer

Abstract Chronic inflammation facilitates the development of cancer, age-related, inflammatory autoimmune and other diseases. Proinflammatory cytokines play a central role in this pathogenic process by driving activation of NF-ƙB, STAT3 and other signaling cascades. IL-22 is an inflammatory cytokine involved in the pathology of autoimmune diseases such as psoriasis, atopic dermatitis, and ulcerative colitis. IL-22 has also been shown to promote epithelial cell proliferation, stemness and tumorigenesis in cancer. Recent studies demonstrated that neutralization of IL-22 reduced dysplasia and tumor development in preclinical models. To date, there has not been a clear application for anti-IL-22 therapy for autoimmune diseases and cancer, likely due to identifying the right disease indication and to their low potency and low efficacy. Thus, there remains an opportunity to explore the potential of more potent anti-IL-22 therapeutics. Using BioAtla’s proprietary antibody discovery and engineering platforms, we have generated humanized anti-IL-22 antibodies with high affinities to human, cynomolgus and mouse IL-22. In vitro data demonstrated that our anti-IL-22 antibodies inhibited IL-22-induced p-STAT3, CXCL-1 and IL-10 activities. In addition, our antibodies showed a 10-fold increased binding activity to human IL-22 compared to Fezakinumab, which was previously developed by Pfizer for the treatment of autoimmune diseases. BioAtla’s high affinity anti-IL-22 antibodies were shown to be more potent relative to Fezakinumab using multiple in vitro assays. To test the functions of our antibodies in vivo, we also established mouse models to determine anti-IL22 efficacy. More specifically, to study whether targeting IL-22 in an inflammation-induced tumor microenvironment reduces tumor occurrence, we developed an inflammation-driven sporadic colitis-associated colorectal cancer mouse model for ongoing cancer studies that will be discussed. In addition, we evaluated our anti-IL22 antibodies in an imiquimod-induced psoriasiform skin inflammation mouse model. The mice treated with potent anti-IL-22 antibodies had significantly reduced skin lesions, including erythema, scales, and skin thickness compared to isotype antibody-treated mice. Q-PCR analysis of the mouse skin demonstrated that treatment with our anti-IL-22 antibody led to significantly decreased RNA levels of the imiquimod-induced inflammatory marker CXCL3. Thus, the enhanced anti-IL-22 therapy is a promising strategy for targeting anti-inflammation in autoimmune diseases, such as psoriasis and atopic dermatitis, and inflammatory cancers, including colorectal cancer. In conclusion, the development of a potent, species cross reactive anti-IL-22 antibody using BioAtla’s antibody discovery and engineering platforms addresses the challenges of anti-IL-22 therapeutics and allows for translational studies in relevant animal efficacy and safety models. Citation Format: Christina Wheeler, Jian Chen, Cathy Chang, Gerhard Frey, Haizhen Liu, Jing Wang, Kathryn Woodard, Solmarie Joyner, Wei Zhou, William J. Boyle, Jay M. Short. Developing anti-IL-22 therapeutics for inflammation and cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6335.

S100A9 Drives the Chronification of Psoriasiform Inflammation by Inducing IL-23/Type 3 Immunity

Psoriasis is a chronic inflammatory skin disorder driven by IL-23/type-3 immune response. However, molecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, confirmed in lesioned skin from psoriasis patients and preclinical psoriasiform skin inflammation models. Genetic ablation or pharmacological inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone-marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type-3 immunity in psoriasiform skin inflammation. Besides, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we demonstrated an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type-3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis.

Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism

The intestinal microbiota has been associated with host immunity as well as psoriasis; however, the mechanism of intestinal microbiota regulating psoriasis needs to be demonstrated systematically. Here, we sought to examine its role and mechanism of action in the pathogenesis of psoriasis. We found that the severity of psoriasis-like skin phenotype was accompanied by changes in the composition of the intestinal microbiota. We performed co-housing and fecal microbial transplantation (FMT) experiments using the K14-VEGF transgenic mouse model of psoriasis and demonstrated that the transfer of intestinal microbiota from mice with severe psoriasis-like skin phenotype exacerbated psoriasiform skin inflammation in mice with mild symptoms, including increasing the infiltration and differentiation of Th17, and increased the abundance of Prevotella, while decreasing that of Parabacteroides distasonis, in the colon. These alterations affected fatty acid metabolism, increasing the abundance of oleic and stearic acids. Meanwhile, gentamicin treatment significantly reduced the abundance of Prevotella and alleviated the psoriasis-like symptoms in both K14-VEGF mice and imiquimod (IMQ)-induced psoriasis-like mice. Indeed, administration of oleic and stearic acids exacerbated psoriasis-like symptoms and increased Th17 and monocyte-derived dendritic cell infiltration in the skin lesion areas in vivo, as well as increased the secretion of IL-23 by stimulating DCs in vitro. At last, we found that, treatment of PDE-4 inhibitor alleviated psoriasis-like phenotype of K14-VEGF mice accompanied by the recovery of intestinal microbiota, including the decrease of Prevotella and increase of Parabacteroides distasonis. Overall, our findings reveal that the intestinal microbiota modulates host metabolism and psoriasis-like skin inflammation in mice, suggesting a new target for the clinical diagnosis and treatment of psoriasis.

Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis.

Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug.

Role of Type I Cannabinoid Receptor in Sensory Neurons in Psoriasiform Skin Inflammation and Pruritus

Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and antipruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in a psoriatic mouse model, whereas CB1R antagonist aggravated these symptoms. Because the expression of CB1R was abundant in dorsal root ganglia, we constructed mice with conditional CB1R knockout in primary sensory neurons and found that imiquimod-induced psoriasiform inflammation and itch were both worsened in CB1R-conditional knockout mice. Next, we observed that the CB1R was mostly located in peptidergic neurons, and deletion of CB1R in primary sensory neurons promoted the production and release of substance P to the skin tissue. Furthermore, the elevated substance P in the skin affected the activation of extracellular signal‒regulated kinase in keratinocytes and induced the accumulation of mast cells in the dermis. Finally, we showed that blocking the substance P signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by imiquimod in CB1R-conditional knockout mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus by regulating substance P expression.

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

Psoriasis arises from poorly defined pathological crosstalk between keratinocytes and the immune system. BCL10 and MALT1 are ubiquitously expressed inflammatory signalling proteins that can interact with the psoriasis susceptibility factor CARD14, but their functions in psoriasis are insufficiently understood. To explore the roles of BCL10 and MALT1 in inflammatory skin diseases, we engineered a series of conditional mouse mutants to specifically activate, inactivate or attenuate BCL10/MALT1 signalling in keratinocytes in vivo.

Discovery and multi-parametric optimization of a high-affinity antibody against interleukin-25 with neutralizing activity in a mouse model of skin inflammation.

BackgroundInterleukin (IL)25 has been implicated in tissue homeostasis at barrier surfaces and the initiation of type two inflammatory signaling in response to infection and cell injury across multiple organs. We sought to discover and engineer a high affinity neutralizing antibody and evaluate the antibody functional activity in vitro and in vivo.MethodsIn this study, we generated a novel anti-IL25 antibody (22C7) and investigated the antibody’s therapeutic potential for targeting IL25 in inflammation.ResultsA novel anti-IL25 antibody (22C7) was generated with equivalent in vitro affinity and potency against the human and mouse orthologs of the cytokine. This translated into in vivo potency in an IL25-induced air pouch model where 22C7 inhibited the recruitment of monocytes, macrophages, neutrophils and eosinophils. Furthermore, 22C7 significantly reduced ear swelling, acanthosis and disease severity in the Aldara mouse model of psoriasiform skin inflammation. Given the therapeutic potential of IL25 targeting in inflammatory conditions, 22C7 was further engineered to generate a highly developable, fully human antibody while maintaining the affinity and potency of the parental molecule.ConclusionsThe generation of 22C7, an anti-IL25 antibody with efficacy in a preclinical model of skin inflammation, raises the therapeutic potential for 22C7 use in the spectrum of IL25-mediated diseases.

KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the Transcription of PIK3R3

The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 invitro and invivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-κB pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.

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

Adiponectin, a hormone secreted from adipocytes, is closely 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. This study aims at confirming the reduction of adiponectin protein level in the human psoriasis skin and investigating whether functional adiponectin replenishment by topical P5 application improves psoriasiform skin inflammation. We examined the adiponectin protein expression in the skin of individuals with psoriasis and normal skin.

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.