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1.
Clin Exp Dermatol ; 49(5): 450-458, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38173286

RESUMO

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.


Assuntos
Antígenos CD1 , Dermatopatias , Linfócitos T , Humanos , Antígenos CD1/metabolismo , Antígenos CD1/imunologia , Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/imunologia , Células de Langerhans/imunologia , Psoríase/imunologia , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Dermatopatias/tratamento farmacológico , Dermatopatias/metabolismo , Dermatopatias/patologia
2.
Arterioscler Thromb Vasc Biol ; 41(3): 1191-1204, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33406853

RESUMO

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/genética , RNA Longo não Codificante/genética , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Células Cultivadas , Colesterol/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/metabolismo , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Regulação para Cima
3.
J Clin Invest ; 129(3): 1115-1128, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30589415

RESUMO

Noncoding RNAs are emerging as important players in gene regulation and disease pathogeneses. Here, we show that a previously uncharacterized long noncoding RNA, nexilin F-actin binding protein antisense RNA 1 (NEXN-AS1), modulates the expression of the actin-binding protein NEXN and that NEXN exerts a protective role against atherosclerosis. An expression microarray analysis showed that the expression of both NEXN-AS1 and NEXN was reduced in human atherosclerotic plaques. In vitro experiments revealed that NEXN-AS1 interacted with the chromatin remodeler BAZ1A and the 5' flanking region of the NEXN gene and that it also upregulated NEXN expression. Augmentation of NEXN-AS1 expression inhibited TLR4 oligomerization and NF-κB activity, downregulated the expression of adhesion molecules and inflammatory cytokines by endothelial cells, and suppressed monocyte adhesion to endothelial cells. These inhibitory effects of NEXN-AS1 were abolished by knockdown of NEXN. In vivo experiments using ApoE-knockout mice fed a Western high-fat diet demonstrated that NEXN deficiency promoted atherosclerosis and increased macrophage abundance in atherosclerotic lesions, with heightened expression of adhesion molecules and inflammatory cytokines, whereas augmented NEXN expression deterred atherosclerosis. Patients with coronary artery disease were found to have lower blood NEXN levels than healthy individuals. These results indicate that NEXN-AS1 and NEXN represent potential therapeutic targets in atherosclerosis-related diseases.


Assuntos
Aterosclerose/metabolismo , Doença da Artéria Coronariana/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas dos Microfilamentos/biossíntese , Placa Aterosclerótica/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Knockout para ApoE , Proteínas dos Microfilamentos/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , RNA Longo não Codificante/genética , Células THP-1
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