RESUMEN
The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of ß-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-ß-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the ß-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-ß-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of ß-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.
Asunto(s)
Proliferación Celular , Reprogramación Celular , Colitis Ulcerosa/metabolismo , Neoplasias Asociadas a Colitis/metabolismo , Enfermedad de Crohn/metabolismo , Epigénesis Genética , Activación de Linfocitos , Linfocitos T Reguladores/metabolismo , Vía de Señalización Wnt , Animales , Estudios de Casos y Controles , Células Cultivadas , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Fenotipo , Factor 1 de Transcripción de Linfocitos T , Linfocitos T Reguladores/inmunologíaRESUMEN
Importance: There were over 45â¯000 suicides in the US in 2020, making suicide the 12th leading cause of death. If social vulnerability is associated with suicide rates, targeted interventions for at-risk segments of the population may reduce US suicide rates. Objective: To determine the association between social vulnerability and suicide in adults. Design, Setting, and Participants: This cohort study analyzed 2 county-level social vulnerability measures (the Social Vulnerability Index [SVI] and the Social Vulnerability Metric [SVM]) and US Centers for Disease Control and Prevention-reported county-level suicides from 2016 to 2020. Data were analyzed November and December 2022. Exposures: County-level variability in social vulnerability. Main Outcomes and Measures: The primary outcome measure was number of county-level adult suicides from 2016 to 2020, offset by county adult population during those years. The association between social vulnerability (measured using the SVI and the newly created SVM for 2018) and suicide was modeled using a bayesian-censored Poisson regression model to account for the CDC's suppression of county-level suicide counts of less than 10, adjusted for age, racial and ethnic minority, and urban-rural county characteristics. Results: From 2016 to 2020, there were a total of 222â¯018 suicides in 3141 counties. Comparing the least socially vulnerable (0% to 10%) to the most socially vulnerable (90% to 100%) counties, there was a 56% increase in suicide rate (17.3 per 100â¯000 persons to 27.0 per 100â¯000 persons) as measured by the SVI (incidence rate ratio, 1.56; 95% credible interval, 1.51-1.60) and an 82% increase in suicide rate (13.8 per 100â¯000 persons to 25.1 per 100â¯000 persons) as measured by the SVM (incidence rate ratio, 1.82; 95% credible interval, 1.72-1.92). Conclusions and Relevance: This cohort study found that social vulnerability had a direct association with risk for adult suicide. Reducing social vulnerability may lead to life-saving reduction in the rate of suicide.