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1.
Geroscience ; 44(3): 1761-1778, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35477832

RESUMO

Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.


Assuntos
Envelhecimento , Inflamação , Gordura Intra-Abdominal , Subpopulações de Linfócitos T , Animais , Inflamação/imunologia , Interleucina-6/metabolismo , Gordura Intra-Abdominal/imunologia , Camundongos , Obesidade/metabolismo , Subpopulações de Linfócitos T/imunologia
2.
Shock ; 55(5): 596-606, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32496420

RESUMO

ABSTRACT: Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with noninflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1ß) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared with control and local inflammation groups. In the omentum, increased expression was limited to IL-1ß, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.


Assuntos
Fatores de Coagulação Sanguínea/fisiologia , Mediadores da Inflamação/fisiologia , Gordura Intra-Abdominal/imunologia , Sepse/sangue , Sepse/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Elife ; 82019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793435

RESUMO

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.


Assuntos
Doenças Mitocondriais/metabolismo , Debilidade Muscular/etiologia , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Sepse/complicações , Animais , Atrofia/etiologia , Atrofia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/metabolismo , Doenças Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Qualidade de Vida
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