naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation.

Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs counteract microbes but are also linked to inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. Here, we report that NET-associated RNA (naRNA) stimulates further NET formation in naive PMNs via a unique TLR8-NLRP3 inflammasome-dependent pathway. Keratinocytes respond to naRNA with expression of psoriasis-related genes (e.g., IL17, IL36) via atypical NOD2-RIPK signaling. In vivo, naRNA drives temporary skin inflammation, which is drastically ameliorated by genetic ablation of RNA sensing. Unexpectedly, the naRNA-LL37 'composite damage-associated molecular pattern (DAMP)' is pre-stored in resting neutrophil granules, defining sterile NETs as inflammatory webs that amplify neutrophil activation. However, the activity of the naRNA-LL37 DAMP is transient and hence supposedly self-limiting under physiological conditions. Collectively, upon dysregulated NET release like in psoriasis, naRNA sensing may represent both a potential cause of disease and a new intervention target.

LL37/self-DNA complexes mediate monocyte reprogramming.

LL37 alone and in complex with self-DNA triggers inflammatory responses in myeloid cells and plays a crucial role in the development of systemic autoimmune diseases, like psoriasis and systemic lupus erythematosus. We demonstrated that LL37/self-DNA complexes induce long-term metabolic and epigenetic changes in monocytes, enhancing their responsiveness to subsequent stimuli. Monocytes trained with LL37/self-DNA complexes and those derived from psoriatic patients exhibited heightened glycolytic and oxidative phosphorylation rates, elevated release of proinflammatory cytokines, and affected naïve CD4+ T cells. Additionally, KDM6A/B, a demethylase of lysine 27 on histone 3, was upregulated in psoriatic monocytes and monocytes treated with LL37/self-DNA complexes. Inhibition of KDM6A/B reversed the trained immune phenotype by reducing proinflammatory cytokine production, metabolic activity, and the induction of IL-17-producing T cells by LL37/self-DNA-treated monocytes. Our findings highlight the role of LL37/self-DNA-induced innate immune memory in psoriasis pathogenesis, uncovering its impact on monocyte and T cell dynamics.

Epidermal proteomics demonstrates Elafin as a psoriasis-specific biomarker and highlights increased anti-inflammatory activity around psoriatic plaques.

BACKGROUND: Eczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different. OBJECTIVE: Further molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data. METHODS: In this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins. RESULTS: Our findings confirmed the psoriasis-associated cytokine IL-36γ as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36γ and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment. CONCLUSIONS: Overall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease.

Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors.

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ-/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.

[Skin reactions related to molluscum contagiosum infection]. / Reacciones cutáneas relacionadas a la infección por molusco contagioso.

Molluscum contagiosum (MC) is a common viral infection in children, immunocompromised, and sexually active adults. Its usual clinical presentation is 2-5 mm, whitish or skin-colored papules, with a shiny surface and central umbilication, generally clustered and randomly distributed over the skin surface. Dermoscopy reveals yellowish-white polylobulated structures with peripheral telangiectasia. Diagnosis is usually clinical supported by dermoscopy. However, in some cases, inflammatory manifestations can be associated with this infection and can mimic other dermatological conditions, making the diagnosis difficult and leading to unnecessary treatments. The objective of this article is to describe the main skin reactions associated with MC infection in order to provide a diagnostic and initial management tool for clinicians dealing with these conditions. Reported manifestations include the BOTE sign, perilesional eczema, Gianotti-Crosti syndrome-like reaction, ID reaction, erythema annulare centrifugum, erythema multiforme, folliculitis, white halo, and atypical manifestations (giant, disseminated, necrotic, polypoidal, and nodular lesions, pseudocysts, abscesses). In pediatric patients with the clinical manifestations described above, infection by molluscum contagiosum pox virus should be considered among the differential diagnoses, and referral to a dermatologist should be made in selected cases.

A simple tool for evaluation of inflammation in psoriasis: Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio as markers in psoriasis patients and related murine models of psoriasis-like skin disease.

Objective parameters to quantify psoriatic inflammation are needed for interdisciplinary patient care, as well as preclinical experimental models. This study evaluates neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in psoriasis patients and five murine models of psoriasis-like skin disease based on topical imiquimod application and overexpression of IL-17A under different promotors. We performed a single-center prospective observational study in a German population, investigating psoriasis patients prior to, 4 weeks, and 16 weeks post begin of systemic anti-inflammatory therapy. Psoriasis area and severity index (PASI), blood count, and C-reactive protein (CRP) levels were attained at each timepoint. Additionally, five murine models of psoriasis-like skin disease involving five distinct experimental procedures differing in time of disease-onset and severity were investigated regarding PLR and NLR. Of 43 recruited psoriasis patients, 34 patients were followed up to 16 weeks. The cohort was 69.77% male, showing a median age of 32.0 years (range 19.0-67.0; IQR 26). The median PASI decreased from 16.35 (8.0-50.0; 10.20) to 1.6 (0-10.3; 2.56) after 16 weeks of systemic therapy. Spearman's correlation showed statistically significant positive correlation for NLR with PASI (rs = 0.27, p = 0.006), however not for PLR. NLR, but not PLR, was significantly associated with PASI in a multiple linear regression analysis including age, sex, psoriasis arthritis, and smoking. In the murine models of psoriasis-like skin disease, both NLR and PLR were significantly increased in the acute-severe models compared to controls (p < 0.001, p = 0.005, and p = 0.02, respectively), demonstrating gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR was significantly associated with PASI in psoriatic patients as well as psoriatic phenotype in different murine psoriasis models. Our data warrants investigation of NLR in psoriasis patients and preclinical psoriasis models as an objective biomarker of psoriatic skin inflammation. KEY MESSAGES : NLR, but not PLR, showed a statistically significant positive correlation with Psoriasis Area and Severity Index (PASI) in our human psoriasis cohort. Both NLR and PLR were significantly increased in murine psoriasis models compared to matched controls, with gradually less increased values from severe-acute to mild-late-onset psoriatic phenotype. NLR may represent an easily available, cheap, and objective parameter to monitor psoriatic inflammation in both clinical patient routine, as well as preclinical experimental murine models.

The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T-cell subsets.

Peripherally-induced regulatory T cells (pTregs) expressing the retinoic acid receptor-related orphan-receptor gamma t (RORγt) are indispensable for intestinal immune homeostasis. Nuclear factor kappa family members regulate the differentiation of thymic Tregs and promote their survival in the periphery. However, the Treg intrinsic molecular mechanisms controlling the size of the pTregs in the intestine and associated lymphoid organs remain unclear. Here, we provide direct evidence that B-cell lymphoma 3 (Bcl3) limits the development of pTregs in a T cell-intrinsic manner. Moreover, the absence of Bcl3 allowed for the formation of an unusual intestinal Treg population co-expressing the transcription factors Helios and RORγt. The expanded RORγt+ Treg populations in the absence of Bcl3 displayed an activated phenotype and secreted high levels of the anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor beta. They were fully capable of suppressing effector T cells in a transfer colitis model despite an intrinsic bias to trans-differentiate toward T helper 17-like cells. Finally, we provide a Bcl3-dependent gene signature in pTregs including altered responsiveness to the cytokines IL-2, IL-6, and tumor necrosis factor alpha. Our results demonstrate that Bcl3 acts as a molecular switch to limit the expansion of different intestinal Treg subsets and may thus serve as a novel therapeutic target for inflammatory bowel disease by restoring intestinal immune tolerance.

IL-17A-driven psoriasis is critically dependent on IL-36 signaling.

Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease's development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses pro-inflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities.

Síndrome de CLOVES: tratamiento con rapamicina oral: reporte de dos casos / CLOVES syndrome: treatment with oral rapamycin: report of two cases

INTRODUCCIÓN: El síndrome de CLOVES se caracteriza por sobrecrecimiento lipomatoso asociado a malformaciones vasculares, representando un desafío diagnóstico y terapéutico. La rapamicina, un inhibidor de la vía mTOR, ha demostrado ser una buena alternativa terapéutica en un grupo de anomalías vasculares. Reportamos dos casos de síndrome de CLOVES con buena respuesta al tratamiento con rapamicina oral. OBJETIVO: Reportar la experiencia del uso de rapamicina oral en el tratamiento de dos pacientes con síndrome de CLOVES. CASOS CLÍNICOS: Caso 1: preescolar femenino de tres años de edad con sín drome de CLOVES e historia de hospitalizaciones reiteradas por infección severa de malformaciones linfáticas macroquísticas y episodios trombóticos. Evoluciona con mala calidad de vida, múltiples hospitalizaciones, riesgo quirúrgico y progresión de las lesiones, por lo que se indicó rapamicina oral. A los 6 meses de tratamiento se evidenció reducción clínica y radiológica del tamaño de las masas lipomatosas y linfáticas, ausencia de linforrea cutánea y mejoría significativa de la calidad de vida, sin requerir nuevas hospitalizaciones. Caso 2: escolar femenino de diez años de edad, portadora de síndrome de CLOVES, que desarrolló escoliosis y deterioro de su capacidad motora, haciéndose dependiente del uso de silla de ruedas. Se indicó rapamicina oral, evidenciándose a los cuatro meses de tratamiento mejoría en su capacidad física, independencia y autovalencia, con desaparición de la linforrea. CONCLUSIÓN: Proponemos la rapamicina oral para el tratamiento de pacientes con sín drome de CLOVES que presenten complicaciones y deterioro de la calidad de vida producto de su enfermedad.

INTRODUCTION: CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malforma tions, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two ca ses of CLOVES syndrome with good response to oral rapamycin treatment. OBJECTIVE: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. CLINICAL CASES: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospita lizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndro me, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and au tonomy, and absence of lymphorrhea after four months of treatment. CONCLUSION: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.

Síndrome de Proteus: reporte de un caso y revisión de la literatura / Proteus syndrome: a case report and literature review

El síndrome de Proteus corresponde a una entidad poco frecuente caracterizada por un sobrecrecimiento progresivo de piel, tejido óseo y adiposo, debido a una mutación somática activante del gen AKT1. Existen distintas manifestaciones cutáneas entre las que se incluyen nevo cerebriforme de tejido conectivo plantar, nevo epidérmico, malformaciones vasculares y trastornos del tejido adiposo que pueden alertar al dermatólogo para poder diagnosticar esta condición, permitiendo un manejo precoz que impida el desarrollo de complicaciones y la muerte temprana. Presentamos el caso de una paciente de 9 años cuya historia clínica y examen físico reflejan los hallazgos clásicos del síndrome de Proteus, recalcando la importancia de un manejo multidisciplinario oportuno.

Proteus syndrome is a rare condition characterized by a progressive overgrowth of skin, bone tissue and adipose tissue, due to an activating somatic mutation of the AKT1 gene. Different cutaneous manifestations that include cerebriform connective tissue nevi, epidermal nevus, vascular malformations and adipose tissue disorders can alert the dermatologist to diagnose this condition, allowing an early management that prevents the complications and early death. We present the case of a 9-year-old patient whose clinical history and physical examination reflect the classic findings of Proteus syndrome, highlighting the importance of a multidisciplinary management.