RESUMO
Adipose tissue resident B cells account for more than 20% of stromal cells within visceral adipose tissues; however, their functions in the adipose tissue niche are poorly elucidated. Here we report that miR-150 modulates adipose tissue function by controlling activation of B cells and their interactions with other immune cells. miR-150KO mice displayed exacerbated obesity-associated tissue inflammation and systemic insulin resistance, which is recapitulated by adoptive transfer of B cells, but not purified immunoglobulin, into obese B(null) mice. Using purified cell populations, we found that enhanced proinflammatory activation of adipose tissue T cells and macrophages was due to miR-150KO B cells action but not cell-autologous mechanisms. miR-150KO B cells displayed significantly enhanced antigen presentation upon stimulation, ultimately leading to elevated inflammation and insulin resistance, compared to wild type B cells. Knockdown of identified miR-150 target genes, Elk1, Etf1 or Myb attenuated B cell action by altering B cell receptor pathways and MHCII cell surface presentation. Our results demonstrate a critical role for miR-150 in regulating B cell functions in adipose tissue which ultimately regulate both metabolic and immunologic homeostasis in the adipose tissue niche.
Assuntos
Linfócitos B/metabolismo , Resistência à Insulina/genética , MicroRNAs/metabolismo , Obesidade/genética , Obesidade/imunologia , Tecido Adiposo/patologia , Animais , Comunicação Celular , Glucose/metabolismo , Células HEK293 , Humanos , Inflamação/genética , Inflamação/patologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Modelos Biológicos , Linfócitos T/metabolismoRESUMO
Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.
Assuntos
Gordura Intra-Abdominal/imunologia , Ativação de Macrófagos/fisiologia , MicroRNAs/fisiologia , PPAR gama/fisiologia , Regiões 3' não Traduzidas/genética , Adipócitos/patologia , Animais , Medula Óssea/patologia , Imunoprecipitação da Cromatina , Dieta Hiperlipídica/efeitos adversos , Deleção de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Genes Reporter , Proteínas de Homeodomínio/fisiologia , Inflamação/imunologia , Inflamação/patologia , Resistência à Insulina , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Pioglitazona , Ligação Proteica , Células Estromais/patologia , Células Th2/imunologia , Tiazolidinedionas/farmacologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteína p120 Ativadora de GTPase/biossíntese , Proteína p120 Ativadora de GTPase/genéticaRESUMO
Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes. Currently available type I interferons for therapeutic immunomodulation are accompanied by high cytotoxicity and therefore in this study we have examined anti-inflammatory effects of interferon tau (IFNT), a member of the type I interferon family with low cellular toxicity even at high doses. Using a diet-induced obesity mouse model, we observed enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, which was accompanied by a significant decrease in secretion of proinflammatory cytokines and elevated anti-inflammatory macrophages (M2) in adipose tissue. Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways. Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.
