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Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released transforming growth factor ß1 (TGF-ß1), which promoted the loss of brown adipocyte identity through aldehyde dehydrogenase 1 family member A1 (Aldh1a1) induction. These findings unfold cell dynamic changes in BAT during obesity and identify LAMs as key responders to tissue metabolic stress and drivers of loss of brown adipocyte identity.
Assuntos
Tecido Adiposo Marrom , Macrófagos , Obesidade , Animais , Obesidade/patologia , Obesidade/metabolismo , Macrófagos/metabolismo , Tecido Adiposo Marrom/metabolismo , Camundongos , Adipócitos Marrons/metabolismo , Camundongos Endogâmicos C57BL , Antígenos CD36/metabolismo , Antígenos CD36/genética , Fator de Crescimento Transformador beta1/metabolismo , Masculino , Lipídeos , Mitocôndrias/metabolismoRESUMO
Adipose tissue macrophages (ATMs) bolster obesity-induced metabolic dysfunction and represent a targetable population to lessen obesity-associated health risks. However, ATMs also facilitate adipose tissue function through multiple actions, including adipocyte clearance, lipid scavenging and metabolism, extracellular remodeling, and supporting angiogenesis and adipogenesis. Thus, high-resolution methods are needed to capture macrophages' dynamic and multifaceted functions in adipose tissue. Herein, we review current knowledge on regulatory networks critical to macrophage plasticity and their multifaceted response in the complex adipose tissue microenvironment.
Assuntos
Adipócitos , Tecido Adiposo , Humanos , Adipogenia , Macrófagos , ObesidadeRESUMO
MicroRNA-150 (miR-150) has been shown to play a general role in the immune system, but very little is known about its role on CD4+ T cell responses. During T cell responses against superantigen Staphylococcal Enterotoxin A, miR-150 expression was down-regulated in antigen-specific CD4+ T cells but up-regulated in CD8+ T cells. CD4+ and CD8+ T cell clonal expansion was greater in miR-150-KO mice than in WT mice, but miR-150 selectively repressed IL-2 production in CD4+ T cells. Transcriptome analysis of CD4+ T cells demonstrated that apoptosis and mTOR pathways were highly enriched in the absence of miR-150. Mechanistic studies confirmed that miR-150 promoted apoptosis specifically in antigen-specific CD4+ T cells, but not in bystander CD4+ nor in CD8+ T cells. Furthermore, inhibition of mTOR-linked mitochondrial superoxidedismutase-2 increased apoptosis in miR-150-/- antigen-specific CD4+ T. Thus, miR-150 impacts CD4+ T cell helper activity by attenuating IL-2 production along with clonal expansion, and suppresses superoxidedismutase to promote apoptosis.
Assuntos
Linfócitos T CD4-Positivos , MicroRNAs , Camundongos , Animais , Linfócitos T CD8-Positivos , Interleucina-2/metabolismo , Regulação para Baixo , Sobrevivência Celular , Serina-Treonina Quinases TOR/metabolismo , MicroRNAs/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Obesity is a prevalent health risk by inducing chronic, low-grade inflammation and insulin resistance, in part from adipose tissue inflammation perpetuated by activated B cells and other resident immune cells. However, regulatory mechanisms controlling B-cell actions in adipose tissue remain poorly understood, limiting therapeutic innovations. MicroRNAs are potent regulators of immune cell dynamics through fine-tuning a network of downstream genes in multiple signaling pathways. In particular, miR-150 is crucial to B-cell development and suppresses obesity-associated inflammation via regulating adipose tissue B-cell function. Herein, we review the effect of microRNAs on B-cell development, activation, and function and highlight miR-150-regulated B-cell actions during obesity which modulate systemic inflammation and insulin resistance. In this way, we hope to promote translational discoveries that mitigate obesity-induced health risks by targeting microRNA-regulated B-cell actions.
RESUMO
Background and Objective: Obesity affects hundreds of millions of people worldwide and is characterized by chronic inflammation and insulin resistance, leading to Type II diabetes and atherosclerotic cardiovascular disease. Extracellular RNAs (exRNAs) are among the components which effect immune actions under obese conditions, and technological advances in recent years have rapidly increased our understanding of their roles and functions. Here we review essential background information on exRNAs and vesicles as well as the impact of immune-derived exRNAs in obesity-related disease. We also offer perspectives on clinical applications of exRNAs and future research directions. Methods: We searched PubMed for articles relevant to immune-derived exRNAs in obesity. Articles written in English and published prior to May 25, 2022 were included. Key Content and Findings: We report findings on the roles of immune-derived exRNAs which are important in obesity-related disease. We also highlight several exRNAs derived from other cell lineages which act on immune cells in metabolic disease. Conclusions: ExRNAs produced by immune cells have profound local and systemic effects under obese conditions and can impact metabolic disease phenotypes. Immune-derived exRNAs represent an important target for future research and therapy.
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Macrophages are widely distributed immune cells that play central roles in a variety of physiologic and pathologic processes, including obesity and cardiovascular disease (CVD). They are highly plastic cells that execute diverse functions according to a combination of signaling and environmental cues. While macrophages have traditionally been understood to polarize to either proinflammatory M1-like or anti-inflammatory M2-like states, evidence has shown that they exist in a spectrum of states between those 2 phenotypic extremes. In obesity-related disease, M1-like macrophages exacerbate inflammation and promote insulin resistance, while M2-like macrophages reduce inflammation, promoting insulin sensitivity. However, polarization markers are expressed inconsistently in adipose tissue macrophages, and they additionally exhibit phenotypes differing from the M1/M2 paradigm. In atherosclerotic CVD, activated plaque macrophages can also exist in a range of proinflammatory or anti-inflammatory states. Some of these macrophages scavenge lipids, developing into heterogeneous foam cell populations. To better characterize the many actions of macrophages in human disease, we have designed a novel set of computational tools: MacSpectrum and AtheroSpectrum. These tools provide information on the inflammatory polarization status, differentiation, and foaming of macrophages in both human and mouse samples, allowing for better characterization of macrophage subpopulations based on their function. Using these tools, we identified disease-relevant cell states in obesity and CVD, including the novel concept that macrophage-derived foam cell formation can follow homeostatic noninflammatory or pathogenic inflammatory foaming programs.
Assuntos
Aterosclerose , Resistência à Insulina , Humanos , Camundongos , Animais , Macrófagos , Inflamação/patologia , Obesidade , Anti-InflamatóriosRESUMO
Obesity-induced adipose tissue dysfunction is bolstered by chronic, low-grade inflammation and impairs systemic metabolic health. Adipose tissue macrophages (ATMs) perpetuate local inflammation but are crucial to adipose tissue homeostasis, exerting heterogeneous, niche-specific functions. Diversified macrophage actions are shaped through finely regulated factors, including microRNAs, which post-transcriptionally alter macrophage activation. Numerous studies have highlighted microRNAs' importance to immune function and potential as inflammation-modulatory. This review summarizes current knowledge of regulatory networks governed by microRNAs in ATMs in white adipose tissue under obesity stress.
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MicroRNAs , Tecido Adiposo/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/metabolismoRESUMO
Macrophages are central players in systemic inflammation associated with obesity and aging, termed meta-inflammation and inflammaging. Activities of macrophages elicited by the two chronic conditions display shared and distinct patterns mechanistically, resulting in multifaceted actions for their pathogenic roles. Drastically expanded tissue macrophage populations under obesity and aging stress attribute to both enhanced recruitment and local expansion. Importantly, molecular networks governing the multifaceted actions of macrophages are directly altered by environmental cues and subsequently contribute to metabolic reprogramming, resulting in meta-inflammation in obesity or inflammaging in aging. In this review, we will summarize how meta-inflammation and inflammaging affect macrophages and the molecular mechanisms involved in these processes.
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Inflamação , Macrófagos , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Envelhecimento/genética , Obesidade/genética , Obesidade/metabolismo , Contagem de LeucócitosRESUMO
Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.
Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Melanoma/terapia , Fosforilação Oxidativa/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Algoritmos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Masculino , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Modelos Genéticos , Avaliação de Resultados em Cuidados de Saúde/métodos , RNA-Seq/métodos , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.
Assuntos
Tecido Adiposo Marrom , Termogênese , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Termogênese/fisiologia , Proteína Desacopladora 1/metabolismoRESUMO
Sterile stimuli can trigger inflammatory responses, and in some cases can lead to a variety of acute or chronic diseases. In this study, we hypothesize that a benzimidazole inhibitor may be used as a therapeutic in the treatment of sterile inflammation. In vitro, this inhibitor blocks TLR signalling and inflammatory responses. The benzimidazole inhibitor does not prevent mouse macrophage activation after stimulation with 2,6,10,14-tetramethylpentadecane (TMPD, also known as pristane), a hydrocarbon oil that mimics features of sterile inflammation when injected in vivo. However, C57BL/6J female mice treated with the benzimidazole inhibitor exhibited a significant reduction of pristane-dependent induction of splenocyte number and weight. Conversely, no significant difference was observed in males. Using mass spectrometry, we found that the urine of pristane-injected mice contained increased levels of putative markers for several inflammatory diseases, which were reduced by the benzimidazole inhibitor. To study the mechanism, we showed that pristane-injected mice had increased cell free DNA in serum, which was not impacted by inhibitor treatment. However, chemokine release (e.g. MCP-1, RANTES and TARC) was significantly reduced in inhibitor-treated mice. Thus, the benzimidazole inhibitor might be used as a new drug to block the recruitment of immune cells during sterile inflammatory diseases in humans.
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Benzimidazóis/administração & dosagem , Citocinas/sangue , Esplenomegalia/tratamento farmacológico , Terpenos/efeitos adversos , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Ácidos Nucleicos Livres/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Esplenomegalia/induzido quimicamente , Esplenomegalia/genética , Esplenomegalia/imunologiaRESUMO
IL-1 receptor-associated kinase (IRAK) 4 is a central enzyme of the TLR pathways. This study tested the hypothesis that IRAK4 kinase activity is prerequisite for regulating innate immunity during infections with intracellular bacteria. To this end, we analyzed responses of macrophages obtained from mice expressing wild-type (WT) IRAK4 or its kinase-inactive K213M mutant (IRAK4KI ) upon infection with intracellular bacteria Listeria monocytogenes or Mycobacterium smegmatis. In contrast to robust induction of cytokines by macrophages expressing kinase-sufficient IRAK4, IRAK4KI macrophages expressed decreased TNF-α, IL-6, IL-1ß, and C-C motif chemokine ligand 5 upon infection with L. monocytogenes or M. smegmatis. Bacterial infection of IRAK4KI macrophages led to attenuated activation of IRAK1, MAPKs and NF-κB, impaired induction of inducible NO synthase mRNA and secretion of NO, but resulted in elevated microbial burdens. Compared with WT animals, systemic infection of IRAK4KI mice with M. smegmatis or L. monocytogenes resulted in decreased levels of serum IL-6 and CXCL-1 but increased bacterial burdens in the spleen and liver. Thus, a loss of IRAK4 kinase activity underlies deficient cytokine and microbicidal responses during infection with intracellular bacteria L. monocytogenes or M. smegmatis via impaired activation of IRAK1, MAPKs, and NF-κB but increases bacterial burdens, correlating with decreased induction of NO.
Assuntos
Imunidade Inata , Síndromes de Imunodeficiência/imunologia , Quinases Associadas a Receptores de Interleucina-1/imunologia , Listeriose/imunologia , Macrófagos/microbiologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Animais , Citocinas/metabolismo , Feminino , Síndromes de Imunodeficiência/genética , Quinases Associadas a Receptores de Interleucina-1/deficiência , Quinases Associadas a Receptores de Interleucina-1/genética , Listeria monocytogenes , Listeriose/enzimologia , Fígado/microbiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Infecções por Mycobacterium não Tuberculosas/enzimologia , Mycobacterium smegmatis , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Doenças da Imunodeficiência Primária , Baço/microbiologiaRESUMO
Schwann cells play a major role in helping heal injured nerves. They help clear debris, produce neurotrophins, upregulate neurotrophin receptors, and form bands of Büngner to guide the healing nerve. But nerves do not always produce enough neurotrophins and neurotrophin receptors to repair themselves. Nerve growth factor (NGF) is an important neurotrophin for promoting nerve healing and lysophosphatidylcholine (LPC) has been shown to stimulate NGF receptors (NGFR). This study tested the administration of a single intraneural injection of LPC (1 mg/mL for single LPC injection and 10 mg/mL for multiple LPC injections) at day 0 and one (day 7), two (days 5 and 7), or three (days 5, 7, and 9) injections of NGF (160 ng/mL for single injections and 80 ng/mL for multiple injections) to determine baseline effects on crushed sciatic nerves in rats. The rats were randomly divided into four groups: control, crush, crush-NGF, and crush-LPC-NGF. The healing of the nerves was measured weekly by monitoring gait; electrophysiological parameters: compound muscle action potential (CMAP) amplitudes; and morphological parameters: total fascicle areas, myelinated fiber counts, fiber densities, fiber packing, and mean g-ratio values at weeks 3 and 6. The crush, crush-NGF, and crush-LPC-NGF groups statistically differed from the control group for all six weeks for the electrophysiological parameters but only differed from the control group at week 3 for the morphological parameters. The crush, crush-NGF, and crush-LPC-NGF groups did not differ from each other over the course of the study. Single injections of LPC and NGF one week apart or multiple treatments of NGF at 5, 7 and 9 days post-injury did not alter the healing rate of the sciatic nerves during weeks 1-6 of the study. These findings are important to define the baseline effects of NGF and LPC injections, as part of a larger effort to determine the minimal dose regimen of NGF to regenerate peripheral nerves.