RESUMEN
Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation in which the body does not reject the organ after discontinuing immunosuppression for at least a year. We revisited the data generated by The Brazilian Multicenter Study on Operational Tolerance involving different conceptual fields - antigen-specific cytokine response, immune cell numbers and repertoire, signaling pathways, and epigenetics. We integrated our data to pave the way to systems biology thinking and harness debate on potential mechanisms in OT. We present original data on systems biology in OT, connecting potential mechanistic players. Using bioinformatics, we identified three dominant features that discriminate OT from its opposing clinical outcome, chronic rejection (CR). The OT-CR discriminative molecules were FOXP3, GATA3 and STAT6, each corresponding to a differential profile: (1) In FOXP3, OT presents preserved regulatory T cell (Treg) numbers but decreased numbers in CR; (2) in GATA3, increased expression is seen in OT; and (3) in STAT6, decreased monocyte activation is seen in OT. With these variables, we built molecular networks to identify interactions related to OT versus CR. Our first systems biology endeavor gave rise to novel potentially relevant interconnected players in OT mechanisms: FOXP3 connecting to interleukin-9 (IL-9) and IL-35 signaling, suggesting their immunoregulatory involvement in OT. Likewise, GATA3/FOXP3 interactions incrementing/stabilizing FOXP3 transcription suggest participation in keeping healthy FOXP3+ Tregs in OT. We envision that systems biology thinking will greatly contribute to advancing knowledge in human transplantation tolerance in an interactive perspective.
Asunto(s)
Trasplante de Riñón , Factores de Transcripción Forkhead/genética , Humanos , Tolerancia Inmunológica , Biología de Sistemas , Linfocitos T Reguladores , Tolerancia al TrasplanteRESUMEN
Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment.
Asunto(s)
Neoplasias de la Mama , Proteína 1 Similar a ELAV , Glutaminasa , Glutaminasa/metabolismo , Glutaminasa/genética , Glutaminasa/antagonistas & inhibidores , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/genética , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , ARN Mensajero/metabolismo , ARN Mensajero/genética , Regulación Neoplásica de la Expresión Génica , Empalme Alternativo , Proliferación Celular , Glutamina/metabolismo , Estabilidad del ARNRESUMEN
Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells' permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.
Asunto(s)
COVID-19/virología , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/virología , Adulto , Anciano , Células CACO-2 , Colon/virología , Células Epiteliales/virología , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Carga Viral , Internalización del Virus , Adulto JovenRESUMEN
Nearly 130 years after the first insights into the existence of mitochondria, new rolesassociated with these organelles continue to emerge. As essential hubs that dictate cell fate, mitochondria integrate cell physiology, signaling pathways and metabolism. Thus, recent research has focused on understanding how these multifaceted functions can be used to improve inflammatory responses and prevent cellular dysfunction. Here, we describe the role of mitochondria on the development and function of immune cells, highlighting metabolic aspects and pointing out some metabolic- independent features of mitochondria that sustain cell function.
Asunto(s)
Inmunidad Adaptativa , Sistema Inmunológico/fisiología , Inmunidad Innata , Mitocondrias/inmunología , Dinámicas Mitocondriales/inmunología , Mitofagia/inmunología , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glucólisis/inmunología , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Mitocondrias/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Oxidación-Reducción , Fosforilación OxidativaRESUMEN
Obesity and insulin resistance have reached epidemic proportions. Obesogenic conditions are associated with increased risk for the development of other comorbidities and obesity-related diseases. In metabolic disorders, there is chronic low-grade inflammation induced by the activation of immune cells, especially in metabolic relevant organs such as white adipose tissue (WAT). These immune cells are regulated by environmental and systemic cues. Ghrelin is a peptide secreted mainly by X/A-like gastric cells and acts through the growth hormone secretagogue receptor (GHS-R). This receptor is broadly expressed in the central nervous system (CNS) and in several cell types, including immune cells. Studies show that ghrelin induces an orexigenic state, and there is increasing evidence implicating an immunoregulatory role for ghrelin. Ghrelin mainly acts on the innate and adaptive immune systems to suppress inflammation and induce an anti-inflammatory profile. In this review, we discuss the immunoregulatory roles of ghrelin, the mechanisms by which ghrelin acts and potential pharmacological applications for ghrelin in the treatment of obesity-associated inflammatory diseases, such as type 2 diabetes (T2D).
Asunto(s)
Inmunidad Adaptativa , Ghrelina/inmunología , Sistema Inmunológico/inmunología , Inmunidad Innata , Inflamación/inmunología , Obesidad/inmunología , Animales , Antiinflamatorios/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Ghrelina/metabolismo , Ghrelina/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Sistema Inmunológico/fisiopatología , Inflamación/metabolismo , Inflamación/fisiopatología , Inflamación/prevención & control , Resistencia a la Insulina , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/fisiopatología , Receptores de Ghrelina/inmunología , Receptores de Ghrelina/metabolismo , Transducción de SeñalRESUMEN
Mesenchymal stem cells (MSCs) are characterized as multipotent stromal cells with the capacity for both self-renewal and differentiation into mesodermal cell lineages. MSCs also have a fibroblast-like phenotype and can be isolated from several tissues. In recent years, researchers have found that MSCs secrete several soluble factors that exert immunosuppressive effects by modulating both innate (macrophages, dendritic and NK cells) and adaptive (B cells and CD4+ and CD8+ T cells) immune responses. This review summarizes the principal trophic factors that are related to immune regulation and secreted by MSCs under both autoimmune and inflammatory conditions. The understanding of mechanisms that regulate immunity in MSCs field is important for their future use as a novel cellular-based immunotherapy with clinical applications in several diseases.