Optimized combination of Cervus nippon (Sika deer), Angelica (Dangui), and Rehmannia (Suk-jihwang) mitigates LPS-induced inflammation: exploring signaling pathways through plasma metabolomics.

This study aimed to determine the optimal combination of three anti-inflammatory materials [i.e., Cervus nippon Temminck (CT), Angelica gigas Nakai (AN), and Rehmannia glutinosa (RG)] for the strongest anti-inflammatory potential. Eighteen combinations of the three materials were tested in LPS-stimulated RAW264.7 cells via assessing nitric oxide (NO). The best combination from in vitro studies was administered to LPS-treated C57BL/6J mice for five days. Subsequently, plasma metabolites were profiled by bioinformatics analyses and validations. As results, 2, 20, and 50 µg/mL of CT, AN, and RG (TM) were the most effective combination suppressing inflammation. In mice, TM mitigated hepatic inflammatory markers. Similarly, the metabolomics indicated that TM may suppress NF-κB signaling pathway, thereby alleviating hepatic inflammation. TM also decreased systemic and hepatic pro-inflammatory cytokines. Collectively, we found the optimal combination of TM for mitigating inflammation; thus further studies on safety, mechanisms, and clinical models are warranted for human applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01476-x.

Epidemiology and Characteristics of Ankle and Foot Injuries in Electric Scooter-Related Accidents.

Background: The use of electric scooters (e-scooters) continues to increase as a simple, inexpensive means of transport, resulting in a sharp increase in the incidence of scooter-related accidents. No study to date has closely examined the injury extent to the lower leg, joints, and extremities from e-scooter-related accidents. Here, we investigated the epidemiology and injury patterns of such accidents, focusing on injuries to the ankle and foot. Methods: Based on data from a single tertiary hospital's database, the demographics of 563 patients with scooter-associated injuries were analyzed retrospectively. Among the patients, 229 patients who were injured by e-scooter riding were further investigated. Based on the data, the general demographics of whole scooter-associated injuries and the injury characteristics and fracture cases of the lower leg, ankle, and foot were analyzed. Results: During the 4-year study period, the number of patients injured by e-scooters increased every year. Lower extremities were the most common injury site (67.2%) among riders, whereas injuries to the head and neck (64.3%) were more common in riders of non-electric scooters. Among the lower leg, ankle, and foot injuries of riders (52 cases), the ankle joint (53.8%) was the most commonly injured site, followed by the foot (40.4%) and lower leg (21.2%). The fracture group scored significantly higher on the Abbreviated Injury Scale than the non-fracture group (p < 0.001). Among the fracture group (20 cases), ankle fractures (9 cases) were most common, including pronation external rotation type 4 injuries (4 cases) and pilon fractures (2 cases). Five patients (25%) had open fractures, and 12 patients (60%) underwent surgical treatment. Conclusions: The ankle and foot are the most common injury sites in e-scooter-related accidents. Given the high frequency and severity of e-scooter-related ankle and foot injuries, we suggest that more attention be paid to preventing these types of injuries with greater public awareness of the dangers of using e-scooters.

High-dimensional profiling of regulatory T cells in psoriasis reveals an impaired skin-trafficking property.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease with a Th17-skewed immune phenotype. Although it has been generally accepted that regulatory T cells (Tregs) in lesional psoriatic skin have functional impairment due to the local inflammatory microenvironment, the molecular properties of skin-homing psoriatic Tregs have not been well explored. METHODS: We designed an extensive 39 marker mass cytometry (CyTOF) panel to deeply profile the immune landscape of skin-homing Tregs from 31 people with psoriasis stratified by psoriasis area severity index score as mild (n = 15) to moderate-severe (n = 16) and 32 healthy controls. We further validated the findings with an in-vitro chemokine-mediated Treg migration assay, immunofluorescent imaging of normal and psoriatic lesional skin and analysed public single-cell RNA-sequencing datasets to expand upon our findings into the local tissue microenvironments. FINDINGS: We discovered an overall decrease in CLAhi Tregs and specifically, CLAhiCCR5+ Tregs in psoriasis. Functional markers CD39 and FoxP3 were elevated in psoriatic Tregs. However, CCR7 expression was significantly increased while CCR4 and CLA expression was reduced in psoriatic Tregs and CLAhi Tregs, which was associated with disease severity. Moreover, psoriatic Tregs revealed increased migratory capacity towards CCR7's ligands, CCL19/CCL21. Interrogation of public single-cell RNA sequencing data confirmed reduced expression of skin-trafficking markers in lesional-skin Tregs compared to non-lesioned skin, further substantiated by immunofluorescent staining. INTERPRETATION: Psoriatic circulating Tregs showed an impaired skin-trafficking phenotype thus leading to insufficient suppression of ongoing inflammation in the lesional skin, expanding upon our current understanding of the impairment of Treg-mediated immunosuppression in psoriasis. FUNDING: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and Information and Communications Technology (2020R1C1C1014513, 2021R1A4A5032185, 2020R1F1A1073692); and the new faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0033).

The Impact of Intervention Design on User Engagement in Digital Therapeutics Research: Factorial Experiment With a Mixed Methods Study.

BACKGROUND: User engagement is crucial for digital therapeutics (DTx) effectiveness; due to variations in the conceptualization of engagement and intervention design, assessment and retention of engagement remain challenging. OBJECTIVE: We investigated the influence of the perceived acceptability of experimental intervention components and satisfaction with core intervention components in DTx on user engagement, while also identifying potential barriers and facilitators to user engagement. METHODS: We conducted a mixed methods study with a 2 × 2 factorial design, involving 12 outpatients with atopic dermatitis. Participants were randomized into 4 experimental groups based on push notification ("basic" or "advanced") and human coach ("on" or "off") experimental intervention components. All participants engaged in self-monitoring and learning courses as core intervention components within an app-based intervention over 8 weeks. Data were collected through in-app behavioral data, physician- and self-reported questionnaires, and semistructured interviews assessed at baseline, 4 weeks, and 8 weeks. Descriptive statistics and thematic analysis were used to evaluate user engagement, perceived acceptability of experimental intervention components (ie, push notification and human coach), satisfaction with core intervention components (ie, self-monitoring and learning courses), and intervention effectiveness through clinical outcomes. RESULTS: The primary outcome indicated that group 4, provided with "advanced-level push notifications" and a "human coach," showed higher completion rates for self-monitoring forms and learning courses compared to the predetermined threshold of clinical significance. Qualitative data analysis revealed three key themes: (1) perceived acceptability of the experimental intervention components, (2) satisfaction with the core intervention components, and (3) suggestions for improvement in the overall intervention program. Regarding clinical outcomes, the Perceived Stress Scale and Dermatology Life Quality Index scores presented the highest improvement in group 4. CONCLUSIONS: These findings will help refine the intervention and inform the design of a subsequent randomized trial to test its effectiveness. Furthermore, this design may serve as a model for broadly examining and optimizing overall engagement in DTx and for future investigation into the complex relationship between engagement and clinical outcomes. TRIAL REGISTRATION: Clinical Research Information Service KCT0007675; http://tinyurl.com/2m8rjrmv.

Skin microbe-dependent TSLP-ILC2 priming axis in early life is co-opted in allergic inflammation.

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood.

A Multicenter Survey of Percutaneous Endoscopic Gastrostomy in 2019 at Korean Medical Institutions.

Background/Aims: : This study aimed to review the indications, methods, cooperation, complications, and outcomes of percutaneous endoscopic gastrostomy (PEG). Methods: : Questionnaires were sent to 200 hospitals, of which 62 returned their questionnaires, with a response rate of approximately 30%. Descriptive statistics were calculated to analyze the responses to the questionnaires. Results: : In 2019, a total of 1,052 PEGs were performed in 1,017 patients at 62 hospitals. The main group who underwent PEG was older adult patients with brain disease, particularly stroke. Nutritional supply was an important purpose of the PEG procedure. "The pull method" was the most commonly used for initial PEG insertion. The complications related to PEG were mostly mild, with leakage being the most common. Patients who underwent PEG procedures were primarily educated regarding the post-procedure management and complications related to PEG. Preoperative meetings were skipped at >50% of the institutions. Regarding the cooperation between the nutrition support team (NST) and the physician performing PEG, few endoscopists answered that they cooperated with NST before and after PEG. Moreover, the rate of NST certification obtained by physicians performing PEG and the frequency of attendance at NST-related conferences were relatively low. Conclusions: : This study shows a similar trend to that found in the previous PEG guidelines. However, it covers new aspects, including team-based work for PEG procedure, nutrition support, and education for patients and guardians. Therefore, each medical institution needs to select an appropriate method considering the medical environment and doctor's abilities.

Identification of dendritic cell precursor from the CD11c+ cells expressing high levels of MHC class II molecules in the culture of bone marrow with FLT3 ligand.

Dendritic cells (DCs) are readily generated from the culture of mouse bone marrow (BM) treated with either granulocyte macrophage-colony stimulating factor (GM-CSF) or FMS-like tyrosine kinase 3 ligand (FLT3L). CD11c+MHCII+ or CD11c+MHCIIhi cells are routinely isolated from those BM cultures and generally used as in vitro-generated DCs for a variety of experiments and therapies. Here, we examined CD11c+ cells in the BM culture with GM-CSF or FLT3L by staining with a monoclonal antibody 2A1 that is known to recognize mature or activated DCs. Most of the cells within the CD11c+MHCIIhi DC gate were 2A1+ in the BM culture with GM-CSF (GM-BM culture). In the BM culture with FLT3L (FL-BM culture), almost of all the CD11c+MHCIIhi cells were within the classical DC2 (cDC2) gate. The analysis of FL-BM culture revealed that a majority of cDC2-gated CD11c+MHCIIhi cells exhibited a 2A1-CD83-CD115+CX3CR1+ phenotype, and the others consisted of 2A1+CD83+CD115-CX3CR1- and 2A1-CD83-CD115-CX3CR1- cells. According to the antigen uptake and presentation, morphologies, and gene expression profiles, 2A1-CD83-CD115-CX3CR1- cells were immature cDC2s and 2A1+CD83+CD115-CX3CR1- cells were mature cDC2s. Unexpectedly, however, 2A1-CD83-CD115+CX3CR1+ cells, the most abundant cDC2-gated MHCIIhi cell subset in FL-BM culture, were non-DCs. Adoptive cell transfer experiments in the FL-BM culture confirmed that the cDC2-gated MHCIIhi non-DCs were precursors to cDC2s, i.e., MHCIIhi pre-cDC2s. MHCIIhi pre-cDC2s also expressed the higher level of DC-specific transcription factor Zbtb46 as similarly as immature cDC2s. Besides, MHCIIhi pre-cDC2s were generated only from pre-cDCs and common DC progenitor (CDP) cells but not from monocytes and common monocyte progenitor (cMoP) cells, verifying that MHCIIhi pre-cDC2s are close lineage to cDCs. All in all, our study identified and characterized a new cDC precursor, exhibiting a CD11c+MHCIIhiCD115+CX3CR1+ phenotype, in FL-BM culture.

Fracture gap and working length are important actionable factors affecting bone union after minimally invasive plate osteosynthesis for the treatment of simple diaphyseal or distal metaphyseal tibia fractures.

INTRODUCTION: Indirect reduction of minimally invasive plate osteosynthesis (MIPO) can often result in delayed union in tibia fractures. This study evaluated several factors in MIPO in relation to bone union. HYPOTHESIS: We hypothesized that the fracture gap, plate - tibia distance, or working length would have a substantial effect on the tibia union rate. MATERIALS AND METHODS: Forty-one patients with simple diaphyseal or distal metaphyseal tibia fractures who underwent internal fixation surgery using the MIPO technique were divided into two groups: patients with delayed union and patients without delayed union. Non-actionable factors involving AO/OTA classification, fibula fracture and actionable factors including postoperative fracture gap, plate - tibia distance, working length in relation to parameters of bone union were compared between the two groups. Also cumulative rates of bone union and risk factors of delayed union according to variables of interest were investigated. RESULTS: AO/OTA classification, site of fibula fracture, postoperative fracture gap, working length, and bone union rate of the two groups significantly differed (p<0.05). The cumulative rate of bone union during 1-year follow-up according to 43A tibia fracture, distal fibula fracture, fracture gap, and working length significantly differed between the two groups (p<0.05). By univariate Cox proportional hazards model, 43A tibia fracture, distal fibula fracture, facture gap, and short working length were risk factors for delayed union (p<0.05). DISCUSSION: Non-actionable factors involving AO/OTA classification, distal fibula fracture and actionable factors including postoperative fracture gap, working length were significant factors affecting bone union after MIPO. The present study indicated that small fracture gap and long working length during MIPO might facilitate bone healing in tibia fracture. LEVEL OF EVIDENCE: IV; single-center retrospective cohort study.

Microenvironmental network of clonal CXCL13+CD4+ T cells and Tregs in pemphigus chronic blisters.

BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-ß stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).

Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G.

Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV's counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base preference for the interaction and a unique Vif-ribose contact. This establishes the biological significance of an RNA ligand. Further assessment of interactions between A3G, Vif, and RNA ligands show that the A3G-Vif assembly and subsequent ubiquitination can be controlled by amino acid mutations at the interface or by polynucleotide modification, suggesting that a specific chemical moiety would be a promising pharmacophore to inhibit the A3G-Vif interaction.

Basic Therapeutic Approach for Patients with Plaque Psoriasis: Korean Expert Consensus Using the Modified Delphi Method.

BACKGROUND: Currently, there is no consensus on the treatment of psoriasis in Korean patients. OBJECTIVE: This study aimed to establish a consensus on the basic therapeutic principles for Korean patients with plaque psoriasis. METHODS: Using the modified Delphi method, a steering committee proposed 53 statements for the first Delphi round, which covered five subjects: (1) the goal of treatment and evaluation of disease severity, (2) topical therapy, (3) phototherapy, (4) conventional systemic therapy, and (5) biologic therapy. The panel of dermatologists scored the level of agreement for each statement on a ten-point scale with scores ranging from 1 (strongly disagree) to 10 (strongly agree). After discussing the results of the first round, the committee reformulated 41 statements. Finally, consensus was defined as more than 70% of the second round scores being ≥7. RESULTS: The panel participants strongly agreed that the ideal treatment goals for Korean patients with plaque psoriasis should include complete skin clearance and high dermatological quality of life. A strong consensus was also reached on the use of topical agents for psoriasis of any severity, the consideration of phototherapy before biologics therapy, the conventional systemic agents for moderate-to-severe psoriasis, and the recommendation of biologic for retractable psoriasis to conventional systemic therapy and phototherapy. CONCLUSION: This modified Delphi panel established an expert consensus on the therapeutic approach for Korean patients with plaque psoriasis. This consensus may improve the treatment outcomes for psoriasis in Korea.

Effects of HAT-CN Layer Thickness on Molecular Orientation and Energy-Level Alignment with ZnPc.

Efficient energy-level alignment is crucial for achieving high performance in organic electronic devices. Because the electronic structure of an organic semiconductor is significantly influenced by its molecular orientation, comprehensively understanding the molecular orientation and electronic structure of the organic layer is essential. In this study, we investigated the interface between a 1,4,5,8,9,11-hexaazatriphenylene hexacarbonitrile (HAT-CN) hole injection layer and a zinc-phthalocyanine (ZnPc) p-type organic semiconductor. To determine the energy-level alignment and molecular orientation, we conducted in situ ultraviolet and X-ray photoelectron spectroscopies, as well as angle-resolved X-ray absorption spectroscopy. We found that the HAT-CN molecules were oriented relatively face-on (40°) in the thin (5 nm) layer, whereas they were oriented relatively edge-on (62°) in the thick (100 nm) layer. By contrast, ZnPc orientation was not significantly altered by the underlying HAT-CN orientation. The highest occupied molecular orbital (HOMO) level of ZnPc was closer to the Fermi level on the 100 nm thick HAT-CN layer than on the 5 nm thick HAT-CN layer because of the higher work function. Consequently, a considerably low energy gap between the lowest unoccupied molecular orbital level of HAT-CN and the HOMO level of ZnPc was formed in the 100 nm thick HAT-CN case. This may improve the hole injection ability of the anode system, which can be utilized in various electronic devices.

Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination.

Generalized bullous fixed drug eruption (GBFDE) is a rare type of life-threatening severe cutaneous adverse reaction that is considered a medical emergency because of its potential lethality. Currently, only a few cases of bullous adverse reactions have been reported after coronavirus disease 2019 (COVID-19) vaccination. We describe a patient with distinct clinical, histopathological, and immunological findings that are consistent with severe GBFDE, after Pfizer messenger RNA COVID-19 vaccination. An 83-year-old man presented with a fever and well-demarcated multiple erythematous patches that occurred only 4 h after receiving the first dose of COVID-19 Pfizer vaccination. Over the next few days, the patches became generalized and turned into blisters covering approximately 30% of the body surface. The patient was started on intravenous methylprednisolone and oral cyclosporine. There were no additional blistering lesions after 10 days of treatment, prompting a gradual dose reduction. Our case suggests that a stepwise vaccination adhering to the standard dosing schedule should be warranted with close monitoring for possible significant side effects.

Elevated serum IgE levels are not associated with poor treatment outcome in psoriasis vulgaris.

Psoriasis is a chronic inflammatory disorder which is associated with impaired skin barrier function. In this context, it was shown that serum IgE level was elevated in significant proportion of psoriasis patients. However, whether serum IgE levels are associated with treatment outcomes of psoriasis has not been understood. We retrospectively analyzed psoriasis patients who visited our clinics through electromedical records. Patients with history of atopic dermatitis were excluded. Total of 483 patients clinically or pathologically diagnosed with psoriasis vulgaris were included for analyses. Initial mean serum IgE level was 226 ± 490.3 KU/L and patients with IgE higher than upper limit normal value were 42.0% (n = 203). Psoriasis Area and Severity Index (PASI) 75 achievement rate according to IgE elevation was analyzed and no statistically meaningful difference was shown. In addition, logistic regression analysis to find out relationship between PASI 75 achievement and IgE titer also failed to show statistically significant relationship. In conclusion, serum IgE level was elevated in significant proportion in the patients with psoriasis, but its elevated level was not associated with treatment outcome.

Risk Factors for Contralateral Tendon Rupture in Patients With Acute Achilles Tendon Rupture.

The present study was performed to determine the incidence and risk factors of contralateral Achilles tendon rupture after an initial tendon rupture, and to identify the associated patient characteristics. Medical records of 181 adult patients with acute Achilles tendon rupture were reviewed. We investigated the risk factors for contralateral Achilles tendon rupture and calculated the incidence density (per 100 person-years), survival rate, hazard ratios, and 95% confidence intervals. The risk factors were extracted, including blood type, age, body mass index (BMI), occupation, underlying comorbidities, history of alcohol intake or smoking, injury mechanism, and fluoroquinolone antibiotic or steroid use. Military personnel and manual laborers, including farmers and firefighters were considered to have an occupation involving physical activity. Ten patients (5.5%) were identified as having nonsimultaneous, contralateral Achilles tendon rupture a mean of 3.3 years (range 1.0-8.3 years) after the initial tendon rupture. The incidence density of contralateral tendon rupture was 0.89 per 100 person-years. The 8-year survival rate of contralateral tendon rupture was 92.2%. Unadjusted and adjusted hazard ratios (with 95% confidence intervals, p value) of blood type O were 3.71 (1.07-12.82, p = .038) and 2.90 (0.81-10.32, p = .101), respectively, and those of occupations involving physical activity were 5.87 (1.64-20.98, p = .006) and 4.69 (1.27-17.28, p = .02), respectively. Based on the present data, blood type O and occupations involving physical activity are significantly associated with an increased risk of contralateral tendon rupture in adult patients who have sustained Achilles tendon rupture.

CTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells.

Dendritic cells are antigen-presenting cells orchestrating innate and adaptive immunity. The crucial role of transcription factors and histone modifications in the transcriptional regulation of dendritic cells has been extensively studied. However, it is not been well understood whether and how three-dimensional chromatin folding controls gene expression in dendritic cells. Here we demonstrate that activation of bone marrow-derived dendritic cells induces extensive reprogramming of chromatin looping as well as enhancer activity, both of which are implicated in the dynamic changes in gene expression. Interestingly, depletion of CTCF attenuates GM-CSF-mediated JAK2/STAT5 signaling, resulting in defective NF-κB activation. Moreover, CTCF is necessary for establishing NF-κB-dependent chromatin interactions and maximal expression of pro-inflammatory cytokines, which prime Th1 and Th17 cell differentiation. Collectively, our study provides mechanistic insights into how three-dimensional enhancer networks control gene expression during bone marrow-derived dendritic cells activation, and offers an integrative view of the complex activities of CTCF in the inflammatory response of bone marrow-derived dendritic cells.

Pellino-1 promotes intrinsic activation of skin-resident IL-17A-producing T cells in psoriasis.

BACKGROUND: Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. Pellino-1 (Peli1) belongs to a member of E3 ubiquitin ligase mediating immune receptor signaling cascades, including nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway. OBJECTIVE: We explored the potential role of Peli1 in psoriatic inflammation in the context of skin-resident T17 cells. METHODS: We performed single-cell RNA sequencing of relapsing and resolved psoriatic lesions with analysis for validation data set of psoriasis. Mice with systemic and conditional depletion of Peli1 were generated to evaluate the role of Peli1 in imiquimod-induced psoriasiform dermatitis. Pharmacologic inhibition of Peli1 in human CD4+ T cells and ex vivo human skin cultures was also examined to evaluate its potential therapeutic implications. RESULTS: Single-cell RNA sequencing analysis revealed distinct T-cell subsets in relapsing psoriasis exhibiting highly enriched gene signatures for (1) tissue-resident T cells, (2) T17 cells, and (3) NF-κB signaling pathway including PELI1. Peli1-deficient mice were profoundly protected from psoriasiform dermatitis, with reduced IL-17A production and NF-κB activation in γδ T17 cells. Mice with conditional depletion of Peli1 treated with FTY720 revealed that Peli1 was intrinsically required for the skin-resident T17 cell immune responses. Notably, pharmacologic inhibition of Peli1 significantly ameliorated murine psoriasiform dermatitis and IL-17A production from the stimulated human CD4+ T cells and ex vivo skin explants modeling psoriasis. CONCLUSION: Targeting Peli1 would be a promising therapeutic strategy for psoriasis by limiting skin-resident T17 cell immune responses.