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1.
Cells ; 10(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34440692

RESUMO

Studies from our laboratory have suggested that activation of αvß3 integrin-mediated signaling could contribute to the fibrotic-like changes observed in primary open angle glaucoma (POAG) and glucocorticoid-induced glaucoma. To determine how αvß3 integrin signaling could be involved in this process, RNA-Seq analysis was used to analyze the transcriptomes of immortalized trabecular meshwork (TM) cell lines overexpressing either a control vector or a wild type (WT) or a constitutively active (CA) αvß3 integrin. Compared to control cells, hierarchical clustering, PANTHER pathway and protein-protein interaction (PPI) analysis of cells overexpressing WT-αvß3 integrin or CA-αvß3 integrin resulted in a significant differential expression of genes encoding for transcription factors, adhesion and cytoskeleton proteins, extracellular matrix (ECM) proteins, cytokines and GTPases. Cells overexpressing a CA-αvß3 integrin also demonstrated an enrichment for genes encoding proteins found in TGFß2, Wnt and cadherin signaling pathways all of which have been implicated in POAG pathogenesis. These changes were not observed in cells overexpressing WT-αvß3 integrin. Our results suggest that activation of αvß3 integrin signaling in TM cells could have significant impacts on TM function and POAG pathogenesis.


Assuntos
Glaucoma de Ângulo Aberto/metabolismo , Integrina alfaVbeta3/metabolismo , Transdução de Sinais , Malha Trabecular/metabolismo , Linhagem Celular Transformada , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glaucoma de Ângulo Aberto/genética , Humanos , Análise de Sequência de RNA
2.
Cell Rep ; 30(4): 1039-1051.e5, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995748

RESUMO

Interleukin-35 (IL-35) is an immunosuppressive cytokine composed of Epstein-Barr-virus-induced protein 3 (Ebi3) and IL-12α chain (p35) subunits, yet the forms that IL-35 assume and its role in peripheral tolerance remain elusive. We induce CBA-specific, IL-35-producing T regulatory (Treg) cells in TregEbi3WT C57BL/6 reporter mice and identify IL-35 producers by expression of Ebi3TdTom gene reporter plus Ebi3 and p35 proteins. Curiously, both subunits of IL-35 are displayed on the surface of tolerogen-specific Foxp3+ and Foxp3neg (iTr35) T cells. Furthermore, IL-35 producers, although rare, secrete Ebi3 and p35 on extracellular vesicles (EVs) targeting a 25- to 100-fold higher number of T and B lymphocytes, causing them to acquire surface IL-35. This surface IL-35 is absent when EV production is inhibited or if Ebi3 is genetically deleted in Treg cells. The unique ability of EVs to coat bystander lymphocytes with IL-35, promoting exhaustion in, and secondary suppression by, non-Treg cells identifies a novel mechanism of infectious tolerance.


Assuntos
Vesículas Extracelulares/metabolismo , Tolerância Imunológica , Subunidade p35 da Interleucina-12/metabolismo , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Receptores de Citocinas/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Técnicas de Cocultura , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/ultraestrutura , Feminino , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Inativação de Genes , Transplante de Coração , Terapia de Imunossupressão , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Linfócitos T Reguladores/metabolismo
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