Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation.

Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis of GEO datasets, we found elevated GSDME levels in psoriatic lesional skin. Additionally, GSDME levels correlated with both psoriasis severity and response to biologics treatments. Single-cell RNA sequencing (scRNA-seq) from a GEO dataset revealed GSDME upregulation in keratinocytes of psoriasis patients. In the imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model, both full-length and cleaved forms of caspase-3 and GSDME were elevated in the epidermis. Abnormal proliferation and differentiation of keratinocytes and dermatitis were attenuated in Gsdme-/- mice and keratinocyte-specific Gsdme conditional knockout mice after IMQ stimulation. Exposure of keratinocytes to mixed cytokines (M5), mimicking psoriatic conditions, led to GSDME cleavage. Moreover, the interaction between GSDME-FL and p65 or c-jun was significantly increased after M5 stimulation. GSDME knockdown inhibited nuclear translocation of p65 and c-jun and decreased upregulation of psoriatic inflammatory mediators such as IL1ß, CCL20, CXCL1, CXCL8, S100A8, and S100A9 in M5-challenged keratinocytes. In conclusion, GSDME in keratinocytes contributes to the pathogenesis and progression of psoriasis, potentially in a pyroptosis-independent manner by interacting and promoting translocation of p65 and c-jun. These findings suggest that keratinocyte GSDME could serve as a potential therapeutic target for psoriasis treatment.

Effect of SARS-CoV-2 infection and vaccine on ovarian reserve: A systematic review.

OBJECTIVE: To evaluate the effect of SARS-CoV-2 infection and vaccination on ovarian reserve. METHODS: Relevant articles were identified in the EMBASE, PubMed, and Web of Science databases from January 2020 to May 2023. Available clinical indicators of ovarian reserve, such as anti-Müllerian hormone (AMH), antral follicle count (AFC), follicle-stimulating hormone (FSH), and estradiol (E2), as well as the time interval from infection or vaccination to measurements, were assessed. RESULTS: Only 2 studies provided evidence that SARS-CoV-2 infection could damage ovarian function. In a comparison of the vaccinated and unvaccinated groups, although 1 prospective cohort study observed the transient statistically significant decrease on serum AMH levels at 3 or 6 months of follow-up, serum AMH levels remained within the normal reserve range (>1.1 ng/dl) throughout the study period. CONCLUSION: Overall, whether ovarian reserve may be affected by SARS-CoV-2 infection remains controversial and further investigations are warranted to clarify this issue. Based on the current evidence, it is safe to assume that COVID-19 vaccination does not exert any adverse effect on ovarian reserve parameters such as AMH, AFC, FSH, and E2, which will provide reassurance for women attempting to fall pregnant.

Oxidative stress induces meiotic defects of oocytes in a mouse psoriasis model.

Psoriasis, an immune-mediated inflammatory disease, is associated with poor pregnancy outcomes. Emerging evidence indicates that these defects are likely attributed to compromised oocyte competence. Nevertheless, little is known about the underlying associated mechanisms between psoriasis and poor oocyte quality. In this study, we construct an imiquimod-induced chronic psoriasis-like mouse model to review the effects of psoriasis on oocyte quality. We discover that oocytes from psoriasis-like mice display spindle/chromosome disorganization, kinetochore-microtubule mis-attachment, and aneuploidy. Importantly, our results show that melatonin supplement in vitro and in vivo not only increases the rate of matured oocytes but also significantly attenuates oxidative stress and meiotic defects by restoring mitochondrial function in oocytes from psoriasis-like mice. Altogether, our data uncover the adverse effects of psoriasis symptoms on oocytes, and melatonin supplement ameliorates oxidative stress and meiotic defects of oocytes from psoriatic mice.

Update on the treatment of multisystem inflammatory syndrome in children associated with COVID-19.

In late 2019, SARS-CoV-2 was detected in China and spread worldwide. In rare cases, children who were infected with COVID-19 may develop multisystem inflammatory syndrome (MIS-C), which could have higher mortality than COVID-19 itself. Therefore, diagnosis and management are critical for treatment. Specifically, most of the initial treatment options of MIS-C choose intravenous immunoglobulin (IVIG) and steroids as the first-line treatment for patients. Moreover, antagonists of some cytokines are used as potential future therapeutics. Of note, therapeutic plasmapheresis can be used as a treatment for refractory severe MIS-C. We believe that each patient, especially those with comorbid conditions, should have individualized treatment based on both multidisciplinary consensus approach and expert opinion.

Dermoscopic features of nail psoriasis: Positive correlation with the severity of psoriasis.

Dermoscopy is an efficient and non-invasive technique which has been widely used in the diagnosis of nail disorders including nail psoriasis (NP). Many nail dermoscopic features are considered as clues to NP. The aim of this study was to investigate specific dermoscopic features of fingernail psoriasis and the correlation between the severity of nail lesions or systemic inflammation, and psoriasis severity of skin and nail. This observational study recruited 135 patients with fingernail psoriasis (1186 fingernails) and 30 patients with onychomycosis (80 fingernails). All of the involved fingernails were examined with a handheld dermatoscope. The Nail Psoriasis Severity Index score (NAPSI) score, Psoriasis Area and Severity Index (PASI) score, body surface area (BSA), and detailed history of patients with psoriasis were recorded. Mann-Whitney U-test, χ2 -test, Spearman's correlation, and Kruskal-Wallis H-test were used for statistical analysis, and the significance threshold was p < 0.05. The trial registration number was 2020-SR-045. We identified onycholysis as the most common feature (93.3%) of fingernail psoriasis. Red lunula, longitudinal fissures, transverse grooves, nail plate crumbling, trachyonychia, oil-dropping sign, erythematous border of an onycholytic area, subungual hyperkeratosis, and dilated streaky capillaries were relevant to NP severity (p < 0.05). Red lunula, transverse grooves, nail plate crumbling, trachyonychia, oil-dropping sign, erythematous border of an onycholytic area, splinter hemorrhages, and dilated streaky capillaries were relevant to systemic inflammation severity (p < 0.05). The total NAPSI score was positively associated with the PASI score and BSA (p < 0.0001). The thumb had a higher NAPSI score than the other fingers (p < 0.05). In conclusion, dermoscopic features can improve the accuracy of diagnosis of nail psoriasis, and have correlations with psoriasis severity.

Acitretin inhibits IL-17A-induced IL-36 expression in keratinocytes by down-regulating IκBζ.

BACKGROUND: IL-36 plays a critical role in aggravating psoriatic inflammation, which is significantly elevated in generalized pustular psoriasis (GPP) compared to psoriasis vulgaris. It is well known that acitretin brings about a rapid and significant effect on the treatment of GPP but not psoriasis vulgaris, whereas the quick therapeutic mechanism of acitretin in GPP has not been fully clarified. OBJECTIVES: We conducted this study to investigate whether acitretin interferes IL-36 expression in keratinocytes. METHOD: We used 100 ng/mL IL-17A and/or various doses of acitretin (0, 0.1, 1, 10 µmol/L) to treat cultured HaCaT cells. We performed Real-time quantitative PCR and ELISA to detect gene and protein expression of IL-36 cytokines, real-time quantitative PCR and Western blot to examine IκBζ. Imiquimod (IMQ)-induced psoriasis-like mouse model was established to evaluate effect of gastrointestinal administrated acitretin. Immunohistochemistry was conducted for effect assessment. RESULTS: Acitretin significantly down-regulated expression of IL-36ß and IL-36γ induced by IL-17A stimulation at both gene and protein levels in HaCaT cells. Acitretin alone had no obvious effect on IL-36 expression in keratinocytes. In IMQ + acitretin group, the skin lesion severity was slightly relieved, however, immunohistochemistry showed IL-36ß and IL-36γ expression in keratinocytes significantly declined in comparison with IMQ group. IL-17A stimulation induced significantly IκBζ expression in HaCaT cells, which could be inhibited by acitretin. CONCLUSION: Acitretin inhibits IL-36 expression induced by IL-17A stimulation in keratinocytes by down-regulating IκBζ, and acitretin significantly inhibits keratinocytes-expressed IL-36ß and IL-36γ in psoriasis-like mouse model, which reveals a new possible mechanism of the notable and quick therapeutic action of acitretin on GPP.