RESUMEN
BACKGROUND: Our previous studies have demonstrated a strong relationship betweenCutibacterium acnes(C. acnes), oxidative stress, and acne inflammation. Syringic acid (SA) is a plant widely used for its antimicrobial, anti-inflammatory, and antioxidant activities, but lacking data on acne. This study aims to investigate the effect and mechanism of SA on acne inflammation induced by C. acnes in vitro and in vivo. METHODS: After using the SA to expose HaCaT keratinocytes, we reevaluated the effect of the SA on cell viability, cell apoptosis, ROS, CAT, SOD, and other inflammatory variables in the heat-killed C. acnes-treated HaCaT cells. Next, to induce mice with acne inflammation, ICR mice were given an intradermal injection of live C. acnes into their right ears. The effect of SA on this inflammation was then examined. Moreover, we explored the mechanism of SA on PPARγ/Nrf2 and NLRP3/caspase-1/IL-1ß pathways by ELISA, immunofluorescence microscopy, and western blot assay. RESULTS: Heat-killed C. acnes triggered remarkable cell apoptosis, ROS production, interleukin (IL)-1ß, IL-18, IL-6, and TNF-α release, reduced SOD and CAT activity, and upregulated the expression of proteins in HaCaT cells, including up-regulating IL-1ß, PPARγ, Nrf2, HO-1, NQO1, NLRP3, and caspase-1, whereas SA inhibited these effects by partially impairing PPARγ activation. In addition, PPARγ silencing decreased C. acnes-induced IL-1ß secretion and the production of intracellular ROS, down-regulating the expression of Nrf2. Nrf2 activator (SFN) enhanced anti-inflammatory activity through antioxidant mechanisms, boosting intracellular ROS production, reducing SOD and CAT activity, and promoting the increase in ROS, HO-1, NQO1, and IL-1ß levels, while PPARγ inhibitor (GW662) effectively inhibited this effect in heat-killed C. acnes-treated cells. Finally, SA also exhibited notable improvements in ear redness, swelling, and the expression of PPARγ, NLRP3, and IL-1ß in vivo. CONCLUSIONS: SA inhibited C. acnes-induced inflammation via regulating the NLRP3/caspase-1/IL-1ß signaling axis by activating the PPARγ/Nrf2-antioxidant pathway, suggesting a new treatment possibility for acne vulgaris.
Asunto(s)
Acné Vulgar , Antiinflamatorios , Caspasa 1 , Ácido Gálico , Interleucina-1beta , Queratinocitos , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , PPAR gamma , Transducción de Señal , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , PPAR gamma/metabolismo , Animales , Caspasa 1/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Transducción de Señal/efectos de los fármacos , Interleucina-1beta/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/microbiología , Acné Vulgar/inmunología , Ratones , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Células HaCaT , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Inflamación/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular , Propionibacterium acnesAsunto(s)
Acné Vulgar , Medicamentos sin Prescripción , Humanos , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/inmunología , Medicamentos sin Prescripción/uso terapéutico , Medicamentos sin Prescripción/efectos adversos , Mercadotecnía , Fármacos Dermatológicos/uso terapéutico , Alérgenos/inmunología , Alérgenos/efectos adversos , Hipersensibilidad a las Drogas/inmunología , Hipersensibilidad a las Drogas/diagnósticoRESUMEN
Acne vulgaris is one of the most common skin diseases. The current understanding of acne primarily revolves around inflammatory responses, sebum metabolism disorders, aberrant hormone and receptor expression, colonization by Cutibacterium acnes, and abnormal keratinization of follicular sebaceous glands. Although the precise mechanism of action remains incompletely understood, it is plausible that macrophages exert an influence on these pathological features. Macrophages, as a constituent of the human innate immune system, typically manifest distinct phenotypes across various diseases. It has been observed that the polarization of macrophages toward the M1 phenotype plays a pivotal role in the pathogenesis of acne. In recent years, extensive research on acne has revealed an increasing number of natural remedies exhibiting therapeutic efficacy through the modulation of macrophage polarization. This review investigates the role of cutaneous macrophages, elucidates their potential significance in the pathogenesis of acne, a prevalent chronic inflammatory skin disorder, and explores the therapeutic mechanisms of natural plant products targeting macrophages. Despite these insights, the precise role of macrophages in the pathogenesis of acne remains poorly elucidated. Subsequent investigations in this domain will further illuminate the pathogenesis of acne and potentially offer guidance for identifying novel therapeutic targets for this condition.
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Acné Vulgar , Macrófagos , Acné Vulgar/inmunología , Acné Vulgar/tratamiento farmacológico , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Animales , Piel/inmunología , Piel/patología , Piel/metabolismoRESUMEN
Acne is a common chronic inflammatory disease of the pilosebaceous unit. Transient receptor potential vanilloid 3 (TRPV3) is an ion channel that is involved in inflammatory dermatosis development. However, the involvement of TRPV3 in acne-related inflammation remains unclear. Here, we used acne-like mice and human sebocytes to examine the role of TRPV3 in the development of acne. We found that TRPV3 expression increased in the skin lesions of Propionibacterium acnes (P. acnes)-injected acne-like mice and the facial sebaceous glands (SGs) of acne patients. TRPV3 promoted inflammatory cytokines and chemokines secretion in human sebocytes and led to neutrophil infiltration surrounding the SGs in acne lesions, further exacerbating sebaceous inflammation and participating in acne development. Mechanistically, TRPV3 enhanced TLR2 level by promoting transcriptional factor phosphorylated-FOS-like antigen-1 (p-FOSL1) expression and its binding to the TLR2 promoter, leading to TLR2 upregulation and downstream NF-κB signaling activation. Genetic or pharmacological inhibition of TRPV3 both alleviated acne-like skin inflammation in mice via the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebaceous inflammation and indicated its potential as an acne therapeutic target.
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Acné Vulgar , Glándulas Sebáceas , Canales Catiónicos TRPV , Receptor Toll-Like 2 , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Animales , Acné Vulgar/metabolismo , Acné Vulgar/patología , Acné Vulgar/genética , Acné Vulgar/inmunología , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Humanos , Ratones , Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/patología , Glándulas Sebáceas/inmunología , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Propionibacterium acnes , Masculino , FN-kappa B/metabolismo , Transducción de Señal , Ratones Endogámicos C57BL , FemeninoRESUMEN
Inflammasomes are multiprotein complexes involved in the host immune response to pathogen infections. Thus, inflammasomes participate in many conditions, such as acne. Recently, it was shown that NETosis, a type of neutrophil cell death, is induced by bacterial infection and is involved in inflammatory diseases such as delayed wound healing in patients with diabetes. However, the relationship between inflammasomes and NETosis in the pathogenesis of inflammatory diseases has not been well studied. In this study, we determined whether NETosis is induced in P. acnes-induced skin inflammation and whether activation of the nucleotide-binding domain, leucine-rich family, and pyrin domain-containing-3 (NLRP3) inflammasome is one of the key factors involved in NETosis induction in a mouse model of acne skin inflammation. We found that NETosis was induced in P. acnes-induced skin inflammation in mice and that inhibition of NETosis ameliorated P. acnes-induced skin inflammation. In addition, our results demonstrated that inhibiting inflammasome activation could suppress NETosis induction in mouse skin. These results indicate that inflammasomes and NETosis can interact with each other to induce P. acnes-induced skin inflammation and suggest that targeting NETosis could be a potential treatment for inflammasome-mediated diseases as well as NETosis-related diseases.
Asunto(s)
Acné Vulgar , Trampas Extracelulares , Inflamasomas , Inflamación , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Inflamasomas/metabolismo , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Acné Vulgar/inmunología , Ratones , Inflamación/inmunología , Inflamación/patología , Piel/patología , Piel/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Ratones Endogámicos C57BL , Humanos , Modelos Animales de EnfermedadRESUMEN
OBJECTIVES: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. METHODS: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. RESULTS: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. CONCLUSION: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.
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Acné Vulgar , Artritis Infecciosa , Modelos Animales de Enfermedad , Inflamasomas , Interferón gamma , Piodermia Gangrenosa , Piodermia Gangrenosa/genética , Humanos , Animales , Ratones , Acné Vulgar/inmunología , Inflamasomas/metabolismo , Inflamasomas/inmunología , Interferón gamma/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Ratones Noqueados , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Retroalimentación Fisiológica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Pirina/genética , Mutación , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Técnicas de Sustitución del Gen , Interleucina-18/metabolismo , Células THP-1RESUMEN
BACKGROUND: Acne vulgaris is a widespread chronic inflammatory dermatological condition. The precise molecular and genetic mechanisms of its pathogenesis remain incompletely understood. This research synthesizes existing databases, targeting a comprehensive exploration of core genetic markers. METHODS: Gene expression datasets (GSE6475, GSE108110, and GSE53795) were retrieved from the GEO. Differentially expressed genes (DEGs) were identified using the limma package. Enrichment analyses were conducted using GSVA for pathway assessment and clusterProfiler for GO and KEGG analyses. PPI networks and immune cell infiltration were analyzed using the STRING database and ssGSEA, respectively. We investigated the correlation between hub gene biomarkers and immune cell infiltration using Spearman's rank analysis. ROC curve analysis validated the hub genes' diagnostic accuracy. miRNet, TarBase v8.0, and ChEA3 identified miRNA/transcription factor-gene interactions, while DrugBank delineated drug-gene interactions. Experiments utilized HaCaT cells stimulated with Propionibacterium acnes, treated with retinoic acid and methotrexate, and evaluated using RT-qPCR, ELISA, western blot, lentiviral transduction, CCK-8, wound-healing, and transwell assays. RESULTS: There were 104 genes with consistent differences across the three datasets of paired acne and normal skin. Functional analyses emphasized the significant enrichment of these DEGs in immune-related pathways. PPI network analysis pinpointed hub genes PTPRC, CXCL8, ITGB2, and MMP9 as central players in acne pathogenesis. Elevated levels of specific immune cell infiltration in acne lesions corroborated the inflammatory nature of the disease. ROC curve analysis identified the acne diagnostic potential of four hub genes. Key miRNAs, particularly hsa-mir-124-3p, and central transcription factors like TFEC were noted as significant regulators. In vitro validation using HaCaT cells confirmed the upregulation of hub genes following Propionibacterium acnes exposure, while CXCL8 knockdown reduced pro-inflammatory cytokines, cell proliferation, and migration. DrugBank insights led to the exploration of retinoic acid and methotrexate, both of which mitigated gene expression upsurge and inflammatory mediator secretion. CONCLUSION: This comprehensive study elucidated pivotal genes associated with acne pathogenesis, notably PTPRC, CXCL8, ITGB2, and MMP9. The findings underscore potential biomarkers, therapeutic targets, and the therapeutic potential of agents like retinoic acid and methotrexate. The congruence between bioinformatics and experimental validations suggests promising avenues for personalized acne treatments.
Asunto(s)
Acné Vulgar , Biología Computacional , Humanos , Acné Vulgar/genética , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/diagnóstico , Acné Vulgar/inmunología , Marcadores Genéticos , Redes Reguladoras de Genes , Mapas de Interacción de Proteínas/genética , Perfilación de la Expresión Génica , Medicina de Precisión , Metotrexato/uso terapéutico , Tretinoina/administración & dosificación , MicroARNs/genética , MicroARNs/metabolismo , Propionibacterium acnes , Células HaCaT , Bases de Datos GenéticasRESUMEN
INTRODUCTION: CircRNAs are closely related to many human diseases; however, their role in acne remains unclear. This study aimed to determine the role of hsa_circ_0102678 in regulating inflammation of acne. METHODS: First, microarray analysis was performed to study the expression of circRNAs in acne. Subsequently, RNase R digestion assay and fluorescence in situ hybridization assay were utilized to confirm the characteristics of hsa_circ_0102678. Finally, qRT-PCR, Western blotting analysis, immunoprecipitation, luciferase reporter assay, circRNA probe pull-down assay, biotin-labeled miRNA pull-down assay, RNA immunoprecipitation assay, and m6A dot blot assay were utilized to reveal the functional roles of hsa_circ_0102678 on inflammation induced by C. acnes biofilm in human primary keratinocytes. RESULTS: Our investigations showed that the expression of hsa_circ_0102678 was significantly decreased in acne tissues, and hsa_circ_0102678 was a type of circRNAs, which was mainly localized in the cytoplasm of primary human keratinocytes. Moreover, hsa_circ_0102678 remarkably affected the expression of IL-8, IL-6, and TNF-α, which induced by C. acnes biofilm. Importantly, mechanistic studies indicated that the YTHDC1 could bind directly to hsa_circ_0102678 and promote the export of N6-methyladenosine-modified hsa_circ_0102678 to the cytoplasm. Besides, hsa_circ_0102678 could bind to miR-146a and sponge miR-146a to promote the expression of IRAK1 and TRAF6. CONCLUSION: Our findings revealed a previously unknown process by which hsa_circ_0102678 promoted keratinocyte inflammation induced by C. acnes biofilm via regulating miR-146a/TRAF6 and IRAK1 axis.
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Acné Vulgar , Péptidos y Proteínas de Señalización Intracelular , Proteínas del Tejido Nervioso , Propionibacteriaceae , Factores de Empalme de ARN , ARN Circular , Humanos , Propionibacteriaceae/fisiología , Acné Vulgar/inmunología , Acné Vulgar/microbiología , Células Cultivadas , Queratinocitos/inmunología , Queratinocitos/microbiología , ARN Circular/genética , Regulación hacia Abajo , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transporte Biológico Activo , Factores de Empalme de ARN/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Objectives: This study aims to describe the characteristics of patients diagnosed with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome at a single center in China and provide an up-to-date literature review. Methods: The clinical data and genotype of three Chinese Han patients were carefully documented and studied. We also conducted a systematic literature review on PAPA syndrome. Results: A total of three patients were diagnosed with PAPA syndrome at our center from 2018 to 2020. Arthritis was observed in all three patients, while pyoderma gangrenosum (PG) was found in two patients and acne in one patient. Other manifestations included pathergy reaction, intermittent fever, oral ulcer, keratitis, proteinuria, and hematuria. The PSTPIP1 A230T mutation was identified in two patients, and a novel Y119C variation was revealed in a sporadic patient. A total of 76 patients with PAPA syndrome reported in 29 articles were included in our literature review. The classical triad of arthritis, PG, and acne was visible in only 16 (25.4%) patients, while 24 (38.1%) exhibited only one major symptom. Skin lesions were more commonly seen in patients with adult-onset disease than those with childhood-onset disease (100 vs. 83%), whereas arthritis was less common (50 vs. 98.1%). Steroid and/or biological agents were effective in most patients. Conclusions: The rarity and phenotypic heterogeneity associated with PAPA syndrome make the diagnosis a huge challenge to physicians, especially in adult patients. A significant portion of patients did not exhibit the full spectrum of the classical triad. Accordingly, gene testing is critically helpful for diagnosis.
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Acné Vulgar/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Artritis Infecciosa/genética , Proteínas del Citoesqueleto/genética , Mutación , Piodermia Gangrenosa/genética , Acné Vulgar/diagnóstico , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/inmunología , Adulto , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/inmunología , Productos Biológicos/uso terapéutico , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Piodermia Gangrenosa/diagnóstico , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/inmunología , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, however the microRNA (miRNA) profile in response to TLR activation and thus the possible role of miRNAs in modulating sebocyte functions has not been elucidated. In this work we identified miR-146a to have the highest induction in the TLR1/2 and 4 activated SZ95 sebocytes and found that its increased levels led to the down-regulation of IL-8 secretion, decreased the chemoattractant potential and stimulated the proliferation of sebocytes. Assessing the gene expression profile of SZ95 sebocytes treated with a miR-146a inhibitor, the induction of GNG7 was one of the highest, while when cells were treated with a miR-146a mimic, the expression of GNG7 was down-regulated. These findings correlated with our in situ hybridization results, that compared with control, miR-146a showed an increased, while GNG7 a decreased expression in sebaceous glands of acne samples. Further studies revealed, that when inhibiting the levels of GNG7 in SZ95 sebocytes, cells increased their lipid content and decreased their proliferation. Our findings suggest, that miR-146a could be a potential player in acne pathogenesis by regulating inflammation, inducing proliferation and, through the indirect down-regulation of GNG7, promoting the lipid production of sebocytes.
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Acné Vulgar/patología , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Inflamación/patología , Lípidos/análisis , Lipogénesis , MicroARNs/genética , Glándulas Sebáceas/patología , Acné Vulgar/genética , Acné Vulgar/inmunología , Acné Vulgar/metabolismo , Adulto , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Subunidades gamma de la Proteína de Unión al GTP/genética , Regulación de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Masculino , RNA-Seq , Glándulas Sebáceas/inmunología , Glándulas Sebáceas/metabolismo , Receptor Toll-Like 1/genética , Receptor Toll-Like 1/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.
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Acné Vulgar/inmunología , Infecciones por Bacterias Grampositivas/inmunología , Mastocitos/inmunología , Propionibacterium acnes/fisiología , Células Th17/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Línea Celular , Biología Computacional , Progresión de la Enfermedad , Citometría de Flujo , Humanos , Memoria Inmunológica , Interleucina-17/metabolismo , Lectinas Tipo C/metabolismo , Activación de Linfocitos , Piel/patologíaRESUMEN
Acne vulgaris is a common inflammatory disease. Among patients with darker skin phototypes (Fitzpatrick III-VI), the inflammatory processes of acne stimulate excess melanogenesis and abnormal melanin deposition, leading to pigmentary sequelae known as post-inflammatory hyperpigmentation and post-inflammatory erythema in all skin tones, although post-inflammatory hyperpigmentation is more common in darker skin and post-inflammatory erythema in lighter skin. These pigmentary alterations can be long lasting and are often more distressing to patients than the active acne lesions. This article discusses what is known about acne-related pigmentation, much of which is extrapolated from general study of nonspecific pigment deposition. Because dyspigmentation poses both a significant clinical concern to patients and a therapeutic challenge to clinicians, we formed a working group consisting of pigmentary experts with the aim of increasing awareness and education of acne-related pigmentary sequelae.
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Acné Vulgar/complicaciones , Hiperpigmentación/terapia , Pigmentación de la Piel/inmunología , Acné Vulgar/inmunología , Antiinflamatorios/uso terapéutico , Terapia Combinada/métodos , Dermabrasión/métodos , Fármacos Dermatológicos/uso terapéutico , Humanos , Hiperpigmentación/inmunología , Hiperpigmentación/patología , Terapia por Luz de Baja Intensidad/instrumentación , Terapia por Luz de Baja Intensidad/métodos , Melaninas/antagonistas & inhibidores , Melaninas/biosíntesis , Piel/inmunología , Piel/patología , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/efectos de la radiaciónRESUMEN
BACKGROUND: Acne vulgaris is a prevalent skin disease lacking effective and well-tolerated treatment. An earlier study indicated that resveratrol (RVT) has therapeutic effects in acne patients through unknown mechanisms. OBJECTIVES: To evaluate the effects of RVT on linoleic acid (LA)-induced lipogenesis and peptidoglycan (PGN)-induced inflammation in cultured SZ95 sebocytes in vitro, and to investigate the underlying mechanisms. METHODS: RNA-sequencing was used to analyze the whole transcriptome. Nile red staining was used to detect intracellular neutral lipids, whereas lipidomics was used to investigate changes in the lipid profile in sebocytes. Interleukin (IL)-1ß and IL-6 mRNA and protein levels were assessed through quantitative real-time PCR and Enzyme-linked immunosorbent assay, respectively. Western blot was used to evaluate the expression of lipogenesis-related proteins, the inflammatory signaling pathway, and the AMP-activated protein kinase (AMPK) pathway. Further, specific small interfering RNA (siRNA) was used to knockdown sirtuin-1 (SIRT1) expression. RESULTS: RVT inhibited the lipogenesis-related pathway and nuclear factor-kappa B (NF-κB) signaling pathway in SZ95 sebocytes. It also downregulated LA-induced lipogenesis, the expression of lipid-related proteins, and the contents of unsaturated fatty acids. Besides, RVT promoted SIRT1 expression and deacetylation of the NF-κB p65 subunit, thereby lowering IL-1ß and IL-6 secretion under PGN induction. Furthermore, pretreatment with AMPK inhibitor Compound C abolished RVT-mediated sebosuppressive and anti-inflammation effects. Meanwhile, SIRT1 silencing abrogated the anti-inflammatory potential of RVT. CONCLUSION: In human SZ95 sebocytes, RVT exhibits sebosuppressive and anti-inflammatory effects partially through the AMPK pathway, which may justify the role of RVT treatment in acne vulgaris.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Acné Vulgar/tratamiento farmacológico , Antiinflamatorios/farmacología , Resveratrol/farmacología , Glándulas Sebáceas/efectos de los fármacos , Acné Vulgar/inmunología , Acné Vulgar/patología , Antiinflamatorios/uso terapéutico , Línea Celular , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/patología , Ácido Linoleico/farmacología , Lipogénesis/efectos de los fármacos , Lipogénesis/inmunología , Peptidoglicano/inmunología , Resveratrol/uso terapéutico , Glándulas Sebáceas/citología , Glándulas Sebáceas/inmunología , Glándulas Sebáceas/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second generation (etretinate and acitretin for psoriasis), a third generation (adapalene and tazarotene) and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.
Asunto(s)
Acné Vulgar/tratamiento farmacológico , Fármacos Dermatológicos/administración & dosificación , Retinoides/administración & dosificación , Acné Vulgar/inmunología , Administración Cutánea , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Fármacos Dermatológicos/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Receptores de Ácido Retinoico/metabolismo , Retinoides/efectos adversos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Receptores Toll-Like/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Acne vulgaris and rosacea are common inflammatory complications of the skin, both characterized by abnormal infiltration of immune cells. The two diseases can be differentiated based on characteristic profile of the immune cell infiltrates at the periphery of disease lesions. In addition, dysregulated infiltration of immune cells not only occur in the acne lesions but also in non-lesional areas of patients with the disease, thus characterizing the immune infiltration in these sites can further enhance our understanding on the pathogenesis of acne. METHODS: Five microarray data-sets (GSE108110, GSE53795, GSE65914, GSE14905 and GSE78097) were downloaded from Gene Expression Omnibus. After removing the batch effects and normalizing the data, we applied the CIBERSORT algorithm combined with signature matrix LM22, to describe 22 types of immune cells' infiltration in acne less than 48 hour (H) old, in comparation with non-lesional skin of acne patients, healthy skin and rosacea (including erythematotelangiectatic rosacea, papulopustular rosacea and phymatous rosacea) and we compared gene expression of Th1 and Th17-related molecules in acne, rosacea and healthy control. RESULTS: Compared with the non-lesional skin of acne patients, healthy individuals and rosacea patients, there is a significant increase in infiltration of neutrophils, monocytes and activated mast cells around the acne lesions, less than 48 H after their development. Contrarily, few naive CD4+ T cells, plasma cells, memory B cells and resting mast cells infiltrate acne sites compared to the aforementioned groups of individuals. Moreover, the infiltration of Regulatory T cells (Tregs) in acne lesions is substantially lower, relative to non-lesional sites of acne patients and skin of healthy individuals. In addition, non-lesional sites of acne patients exhibit lower infiltration of activated memory CD4+ T cells, plasma cells, memory B cells, M0 macrophages, neutrophils, resting mast cells but higher infiltration of Tregs and resting dendritic cells relative to skin of healthy individuals. Intriguingly, we found that among the 3 rosacea subtypes, the immune infiltration profile of papulopustular rosacea is the closest to that of acne lesions. In addition, through gene expression analysis of acne, rosacea and skin tissues of healthy individuals, we found a higher infiltration of Th1 and Th17 cells in acne lesions, relative to non-lesional skin areas of acne patients. CONCLUSIONS: Our study provides new insights into the inflammatory pathogenesis of acne, and the difference between acne and rosacea, which helps in differentiating the two diseases. Our findings also guide on appropriate target therapy of the immune cell infiltrates in the two disease conditions.
Asunto(s)
Biología Computacional/métodos , Rosácea/inmunología , Células TH1/inmunología , Células Th17/inmunología , Acné Vulgar/inmunología , Acné Vulgar/patología , Expresión Génica , Humanos , Rosácea/patología , Células TH1/citología , Células Th17/citologíaRESUMEN
Cutibacterium acnes (formerly Propionibacterium acnes) is one of the major bacterial species responsible for acne vulgaris. Numerous bioactive compounds from Momordica charantia Linn. var. abbreviata Ser. have been isolated and examined for many years. In this study, we evaluated the suppressive effect of two cucurbitane-type triterpenoids, 5ß,19-epoxycucurbita-6,23-dien-3ß,19,25-triol (Kuguacin R; KR) and 3ß,7ß,25-trihydroxycucurbita-5,23-dien-19-al (TCD) on live C. acnes-stimulated in vitro and in vivo inflammatory responses. Using human THP-1 monocytes, KR or TCD suppressed C. acnes-induced production of interleukin (IL)-1ß, IL-6 and IL-8 at least above 56% or 45%, as well as gene expression of these three pro-inflammatory cytokines. However, a significantly strong inhibitory effect on production and expression of tumor necrosis factor (TNF)-α was not observed. Both cucurbitanes inhibited C. acnes-induced activation of the myeloid differentiation primary response 88 (MyD88) (up to 62%) and mitogen-activated protein kinases (MAPK) (at least 36%). Furthermore, TCD suppressed the expression of pro-caspase-1 and cleaved caspase-1 (p10). In a separate study, KR or TCD decreased C. acnes-stimulated mouse ear edema by ear thickness (20% or 14%), and reduced IL-1ß-expressing leukocytes and neutrophils in mouse ears. We demonstrated that KR and TCD are potential anti-inflammatory agents for modulating C. acnes-induced inflammation in vitro and in vivo.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Cucurbitacinas/química , Cucurbitacinas/farmacología , Inflamación/tratamiento farmacológico , Momordica charantia/química , Triterpenos/química , Triterpenos/farmacología , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/inmunología , Acné Vulgar/microbiología , Animales , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Glicósidos/química , Glicósidos/farmacología , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/inmunología , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Masculino , Ratones , Ratones Endogámicos ICR , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Propionibacteriaceae/patogenicidad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células THP-1RESUMEN
TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17-secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, which we correlated by RNA sequencing to the expression of transcripts encoding proteins that contribute to antimicrobial activity. Additionally, we validated that AMTH17-mediated killing of C. acnes and bacterial pathogens was dependent on the secretion of granulysin, granzyme B, perforin, and histone H2B. We found that AMTH17 cells can release fibrous structures composed of DNA decorated with histone H2B that entangle C. acnes that we call T cell extracellular traps (TETs). Within acne lesions, H2B and IL-17 colocalized in CD4+ T cells, in proximity to TETs in the extracellular space composed of DNA decorated with H2B. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to form TETs containing secreted antimicrobial proteins that capture and kill bacteria.
Asunto(s)
Acné Vulgar/inmunología , Trampas Extracelulares/inmunología , Propionibacteriaceae/inmunología , Enfermedades Cutáneas Bacterianas/inmunología , Células Th17/inmunología , Acné Vulgar/microbiología , Humanos , RNA-Seq , Enfermedades Cutáneas Bacterianas/microbiologíaRESUMEN
Cutibacterium (previously Propionibacterium) acnes is an anaerobic, Gram-positive commensal of the human body. The bacterium has been associated with a variety of diseases, including acne vulgaris, prosthetic joint infections, prostate cancer, and sarcoidosis. The accumulation of C. acnes in diseases such as acne and prostate cancer has been shown to correlate with enhanced inflammation. While the C. acnes-induced proinflammatory axis, via NF-κB and MAPK signaling and inflammasome activation, has been investigated over the last few decades, the potential role of C. acnes in triggering the type I interferon (IFN-I) pathway has not been addressed. Our results show that C. acnes induces the IFN-I signaling axis in human macrophages by triggering the cGAS-STING pathway. In addition, IFN-I signaling induced by C. acnes strongly depends on the adapter protein TRIF in a non-canonical manner; these signaling events occurred in the absence of any detectable intracellular replication of the bacterium. Collectively, our results provide important insight into C. acnes-induced intracellular signaling cascades in human macrophages and suggest IFN-I as a factor in the etiology of C. acnes-induced diseases. This knowledge may be valuable for developing novel therapies targeting C. acnes in diseases where the accumulation of the bacterium leads to an inflammatory pathology.
Asunto(s)
Acné Vulgar/inmunología , Infecciones por Bacterias Grampositivas/inmunología , Interferón Tipo I/metabolismo , Macrófagos/inmunología , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/metabolismo , Propionibacteriaceae/fisiología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , AMP Cíclico/metabolismo , Humanos , Inmunidad Innata , Inflamasomas/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Células THP-1RESUMEN
Acne is a common inflammatory skin disease with the dysregulation of innate and adaptive immunity. However, the underlying mechanism of acne has not been completely elucidated. In this study, we identified gene signatures and the immune-related regulatory network in acne using integrated bioinformatics methods. Here, 303 Differentially expressed genes (DEGs) and 28 Hub genes were identified in acne (GSE53795 and GSE108110), which were associated with the inflammation-related signaling pathway. Subsequently, the CIBERSORT algorithm revealed the increased proinflammatory cells in acne. Moreover, we identified 3 kinases (FGR, HCK and LYN) and 2 transcription factors (TFs) (IRF8 and ZBTB16) from DEGs as the key genes, which regulated immune cell infiltration via targeting immune-related genes in acne. The upregulated 3 kinases (FGR, HCK and LYN) and IRF8, and the downregulated ZBTB16 were also confirmed in GSE6475 and in Acne mice. Based on the expression levels of these key genes, the tissues could be divided into 2 clusters using consensus cluster analysis. GSEA analysis showed that inflammation-related signaling pathways significantly enriched in cluster 2, indicating the important role of kinase and TFs on immune regulation in acne. Finally, we found that isotretinoin and trifarotene (CD5789) treatment repressed the expression of immune genes but not the expression of the kinases and TFs, indicating that kinases and TFs may be novel therapeutic target for acne. In conclusion, 3 kinases and 2 TFs were identified and validated as key regulators in the immune-related regulatory networks in acne, providing a more comprehensive understanding and novel therapeutic targets of acne.
Asunto(s)
Acné Vulgar/genética , Acné Vulgar/inmunología , Regulación de la Expresión Génica , Acné Vulgar/tratamiento farmacológico , Animales , Análisis por Conglomerados , Biología Computacional/métodos , Bases de Datos Genéticas , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Isotretinoína/administración & dosificación , Isotretinoína/farmacología , Ratones Endogámicos BALB C , Fosfotransferasas/efectos de los fármacos , Fosfotransferasas/genética , Fosfotransferasas/inmunología , Mapas de Interacción de Proteínas/inmunología , Retinoides/administración & dosificación , Retinoides/farmacología , Transducción de Señal , Piel/efectos de los fármacos , Piel/inmunología , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Transcriptoma/inmunologíaRESUMEN
Our understanding of the role of Cutibacterium acnes in the pathophysiology of acne has recently undergone a paradigm shift: rather than C. acnes hyperproliferation, it is the loss of balance between the different C. acnes phylotypes, together with a dysbiosis of the skin microbiome, which results in acne development. The loss of diversity of C. acnes phylotypes acts as a trigger for innate immune system activation, leading to cutaneous inflammation. A predominance of C. acnes phylotype IA1 has been observed, with a more virulent profile in acne than in normal skin. Other bacteria, mainly Staphylococcus epidermis, are also implicated in acne. S. epidermidis and C. acnes interact and are critical for the regulation of skin homeostasis. Recent studies also showed that the gut microbiome is involved in acne, through interactions with the skin microbiome. As commonly used topical and systemic antibiotics induce cutaneous dysbiosis, our new understanding of acne pathophysiology has prompted a change in direction for acne treatment. In the future, the development of individualized acne therapies will allow targeting of the pathogenic strains, leaving the commensal strains intact. Such alternative treatments, involving modifications of the microbiome, will form the next generation of 'ecobiological' anti-inflammatory treatments.