RESUMO
Integrins are adhesion molecules critical for the recruitment of leukocytes from blood into peripheral tissues. However, whether integrins are also involved in leukocyte exit from peripheral tissues via afferent lymphatics to the draining lymph node remains poorly understood. In this article, we show that adhesion by the collagen IV-binding integrin α1ß1 unexpectedly inhibited macrophage exit from inflamed skin. We monitored macrophages exiting mouse footpads using a newly developed in situ pulse labeling technique. Blockade of α1ß1 integrin or genetic deletion (Itga1(-/-)) increased macrophage exit efficiency. Chemotaxis assays through collagen IV showed more efficient migration of Itga1(-/-) macrophages relative to wild type. Given that macrophages are key orchestrators of inflammation, α1ß1 integrin adhesion may represent a mechanism for regulating inflammatory responses by controlling macrophage exit or persistence in inflamed tissues.
Assuntos
Inibição de Migração Celular/imunologia , Mediadores da Inflamação/fisiologia , Integrina alfa1beta1/fisiologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Adesão Celular/genética , Adesão Celular/imunologia , Inibição de Migração Celular/genética , Pé , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Cadeias alfa de Integrinas/biossíntese , Cadeias alfa de Integrinas/deficiência , Cadeias alfa de Integrinas/genética , Integrina alfa1beta1/biossíntese , Integrina alfa1beta1/deficiência , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/fisiologiaRESUMO
Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3(-/-), E4BP4(-/-)) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.
Assuntos
Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Doenças Transmissíveis/imunologia , Imunidade Celular/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica , Análise de Variância , Animais , Testes Imunológicos de Citotoxicidade , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Técnicas Histológicas , Interferon-alfa/metabolismo , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Major hemorrhage is a significant contributor to the morbidity and mortality resulting from traumatic injury. In addition to its role in in early mortality, hemorrhagic shock followed by resuscitation (HS/R) is known to initiate immunological events that contribute to the development of organ dysfunction. The pathogenesis of acute lung injury following HS/R involves macrophage activation. Recent studies have shown that macrophage function may in part be regulated by polarization toward classical M1 pro-inflammatory cells or alternatively activated anti-inflammatory M2 cells. We hypothesized that alteration in the M1/M2 phenotypic balance of alveolar macrophages in the lung may contribute to a pro-inflammatory state following HS/R. Using a murine model, we show that HS/R causes a rapid reduction in surface cluster of differentiation (CD)206 and CD36, markers of M2 cells, as well as in CD206 messenger ribonucleic acid (mRNA). M1 markers including surface CD80 and tumour necrosis factor alpha and inducible nitric oxide synthase mRNA were increased, albeit in a somewhat delayed time course. The prostaglandin 5-deoxyDelta12,14 prostaglandin J2 (15d-PGJ2), known to polarize cells toward M2, restored levels of M2 macrophages toward control and prevented lung injury, as assessed by bronchoalveolar protein content. Adoptive cell transfer of in vitro M2 polarized macrophages also reduced lung inflammation/injury following hemorrhagic shock. Together, these studies demonstrate that HS/R increases M1/M2 ratio, predominantly by lowering M2 cells, and thus enhances the proinflammatory state. Various strategies aimed at promoting M2 polarization may lessen the magnitude of inflammation and injury. This represents a novel approach to the prevention/treatment of lung injury in critically ill trauma patients.
Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos/toxicidade , Macrófagos Alveolares , Ressuscitação , Choque Hemorrágico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Animais , Antígenos de Diferenciação/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Choque Hemorrágico/metabolismo , Choque Hemorrágico/terapiaRESUMO
The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA+ immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA+ immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA+ B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.
Assuntos
Imunoglobulina A/imunologia , Resistência à Insulina , Obesidade/imunologia , Tecido Adiposo/imunologia , Animais , Linfócitos B/imunologia , Estudos de Coortes , Fezes/microbiologia , Microbioma Gastrointestinal , Glucose/metabolismo , Humanos , Intestinos/imunologia , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/microbiologiaRESUMO
Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, while IFNαR1-/- mice, or CD8-specific IFNαR1-/- chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.
RESUMO
Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.
Assuntos
Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina/fisiologia , Ácidos Nucleicos/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Adulto , Animais , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Dieta Hiperlipídica/métodos , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores Toll-Like/metabolismoRESUMO
Excess energy intake and a sedentary lifestyle have led to increasing incidence of obesity which is a major risk factor for the development of insulin resistance. Research in the last two decades has revealed that chronic-low grade inflammation in adipose tissue is a key link between obesity and insulin resistance. As a result, adipose tissue is now considered an active immune organ with a key role in metabolic homeostasis. In the course of obesity, cells of the immune system infiltrate visceral adipose tissue (VAT) in an active process that promotes local and systemic inflammation. This inflammatory process in VAT is driven by various subsets of immune cells and is a central mechanism connecting obesity with its metabolic complications. One key event of adipose tissue inflammation is the switching of macrophages towards a pro-inflammatory phenotype. In addition, recent research has discovered an expanding list of immune cells contributing to this inflammatory process. Pro-inflammatory immune cells are crucial to obese VAT inflammation because of their production of cytokines, which can interfere with insulin signaling in peripheral tissues. This review summarizes our current knowledge of the pathology of innate and adaptive immune cells in obese adipose tissue, with emphasis in the immunological mechanisms mediating obesity-associated insulin resistance.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Gordura Intra-Abdominal/patologia , Síndrome Metabólica/patologia , Obesidade/patologia , Paniculite/patologia , Animais , Metabolismo Energético , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Paniculite/imunologia , Paniculite/metabolismo , Transdução de SinaisRESUMO
Obesity-related insulin resistance is associated with an influx of pathogenic T cells into visceral adipose tissue (VAT), but the mechanisms regulating lymphocyte balance in such tissues are unknown. Here we describe an important role for the immune cytotoxic effector molecule perforin in regulating this process. Perforin-deficient mice (Prf1(null)) show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD). Regulatory effects of perforin on glucose tolerance are mechanistically linked to the control of T-cell proliferation and cytokine production in inflamed VAT. HFD-fed Prf1(null) mice have increased accumulation of proinflammatory IFN-γ-producing CD4(+) and CD8(+) T cells and M1-polarized macrophages in VAT. CD8(+) T cells from the VAT of Prf1(null) mice have increased proliferation and impaired early apoptosis, suggesting a role for perforin in the regulation of T-cell turnover during HFD feeding. Transfer of CD8(+) T cells from Prf1(null) mice into CD8-deficient mice (CD8(null)) resulted in worsening of metabolic parameters compared with wild-type donors. Improved metabolic parameters in HFD natural killer (NK) cell-deficient mice (NK(null)) ruled out a role for NK cells as a single source of perforin in regulating glucose homeostasis. The findings support the importance of T-cell function in insulin resistance and suggest that modulation of lymphocyte homeostasis in inflamed VAT is one possible avenue for therapeutic intervention.
Assuntos
Intolerância à Glucose/imunologia , Resistência à Insulina/imunologia , Gordura Intra-Abdominal/imunologia , Obesidade/imunologia , Paniculite/imunologia , Perforina/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Dieta Hiperlipídica , Células-Tronco Embrionárias/citologia , Feminino , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Insulina/metabolismo , Gordura Intra-Abdominal/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Paniculite/genética , Paniculite/metabolismo , Perforina/genética , Perforina/metabolismo , Baço/citologia , Baço/imunologiaRESUMO
Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.
Assuntos
Anti-Inflamatórios/farmacologia , Trato Gastrointestinal/imunologia , Imunidade nas Mucosas/imunologia , Resistência à Insulina/imunologia , Obesidade/imunologia , Animais , Western Blotting , Citocinas/sangue , Dieta Hiperlipídica/efeitos adversos , Citometria de Fluxo , Trato Gastrointestinal/efeitos dos fármacos , Técnicas Histológicas , Imuno-Histoquímica , Cadeias beta de Integrinas/metabolismo , Mesalamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Mucosa/citologia , Mucosa/imunologiaRESUMO
The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNγ upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity.