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Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis., (© 2024. The Author(s).)

Background: The phase 3 studies, VOYAGE 1 and 2, were conducted to assess guselkumab in the treatment of patients with moderate-to-severe psoriasis., Objectives: To investigate the efficacy and safety of guselkumab in Korean patients., Methods: The Korean sub-population of VOYAGE 1 and 2 study patients were included in this analysis. Efficacy and safety were evaluated through Weeks 24 and 28, respectively., Results: Of 126 randomized Korean patients, 30, 63, and 33 received placebo, guselkumab, and adalimumab, respectively. At Week 16, guselkumab was superior to placebo in achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (cleared or minimal; 90.5 vs. 20.0%, p <.001) and a Psoriasis Area and Severity Index (PASI) 90 response (71.4 vs. 3.3%, p <.001). At week 24, a significantly higher proportion of guselkumab-treated patients achieved PASI 75 and IGA 0 (clear skin) responses compared to adalimumab-treated patients (PASI 75: 93.7 vs. 66.7%, p <.001; IGA 0: 52.4 vs. 21.2%, p =.004). Through Week 28, guselkumab and adalimumab showed comparable safety profiles., Conclusion: The efficacy and safety of guselkumab in Korean psoriasis patients through 28 weeks were consistent with findings for the overall VOYAGE 1 and 2 study population.

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27 Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27 Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.

Eosinophils are proinflammatory granulocytes that are involved in the pathogenesis of various inflammatory reactions. However, their roles in psoriasis remain largely unknown. In this study, by examining the inflammatory features of the eosinophilic cell line EoL-1 and an imiquimod-induced murine model of psoriasis, we show that eosinophils provide inflammatory signals that accelerate the pathogenesis of psoriasis. EoL-1 cells constitutively expressed TLR7, which mediates acute and rapidly developing psoriatic inflammation. The activation of TLR7 on EoL-1 cells using R837 resulted in the secretion of inflammatory mediators that support the migration, activation, and survival of neutrophils. The underlying pathologic role of eosinophils in psoriatic inflammation was further substantiated by markedly decreased psoriasiform inflammation in imiquimod-treated ΔdblGATA mice, which have a systemic eosinophil deficiency. While imiquimod-treated wild-type mice showed a significant increase in the eosinophils in their skin, neutrophils remarkably outnumbered the eosinophils in the skin, lymph nodes, and spleen in wild-type mice after imiquimod application. In addition, lesional skin samples from psoriasis patients also showed up-regulated eosinophil cytotoxic granules, accompanied by marked neutrophil infiltration. Based on these collective data, we propose that eosinophils accelerate psoriatic inflammation by supporting inflammatory microenvironments to favor the activation and infiltration of neutrophils., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

While ustekinumab has been widely used as an effective biologic for the treatment of chronic plaque psoriasis, no prospective studies have specifically investigated the clinical factors that may influence treatment outcomes with ustekinumab. This post-hoc analysis aimed to identify specific clinical factors that may influence treatment outcomes with ustekinumab in psoriasis patients. In the MARCOPOLO study, 102 Korean patients with moderate to severe psoriasis were analyzed to assess the influence of baseline characteristics as clinical factors on clinical response (improvement in Psoriasis Area and Severity Index by ≥75%/90% [PASI75/PASI90]) to ustekinumab. In addition, differences in PASI75 and PASI90 responses between the responder group and non-responders were evaluated at weeks 28 and 52. Multiple logistic regression analysis was used to determine adjusted clinical factors predicting treatment outcomes among patient characteristics. At week 28, there was a significant difference in PASI75/PASI90 response based on prior biologic experience, although the difference did not persist at week 52. In addition, after adjusting for the effects of relevant clinical factors, biologic experience was significantly associated with less PASI75 (odds ratio [OR] = 0.14, P = 0.001) and PASI90 (OR = 0.22, P = 0.036) responses at week 28. The presence of comorbidities was higher among non-responders than among PASI75/PASI90 responders at both weeks 28 and 52, but was not statistically significant. Previous biologic use was the only clinical factor predicting less response at week 28, although it did not influence the clinical response after week 52. Further studies are warranted to investigate the association between presence of comorbidities and clinical response., (© 2016 Japanese Dermatological Association.)