RESUMO
Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.
Assuntos
Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/complicações , Cirrose Hepática/complicações , Hepatite B/complicaçõesRESUMO
Adipose tissue inflammation has been implicated in various chronic inflammatory diseases and cancer. Perivascular adipose tissue (PVAT) surrounds the aorta as an extra layer and was suggested to contribute to atherosclerosis development. PVAT regulates the function of endothelial and vascular smooth muscle cells in the aorta and represent a reservoir for various immune cells which may participate in aortic inflammation. Recent studies demonstrate that adipocytes also express various cytokine receptors and, therefore, may directly respond to inflammatory stimuli. Here we will summarize current knowledge on immune mechanisms regulating adipocyte activation and the crosstalk between myeloid cells and adipocytes in pathogenesis of atherosclerosis.
Assuntos
Tecido Adiposo , Aterosclerose , Humanos , Tecido Adiposo/patologia , Adipócitos/patologia , Aterosclerose/patologia , Inflamação , Células Mieloides/patologiaRESUMO
Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy that is commonly associated with a life-threatening thrombocytopenic condition, Kasabach-Merritt phenomenon (KMP). Platelet CLEC-2, tumor podoplanin interaction is considered the key mechanism of platelet clearance in these patients. Here, we aimed to assess platelet functionality in such patients. Three groups of 6 to 9 children were enrolled: group A with KHE/KMP without hematologic response (HR) to therapy; group B with KHE/KMP with HR; and group C with healthy children. Platelet functionality was assessed by continuous and end point flow cytometry, low-angle light scattering analysis (LaSca), fluorescent microscopy of blood smears, and ex vivo thrombi formation. Platelet integrin activation in response to a combination of CRP (GPVI agonist) and TRAP-6 (PAR1 agonist), as well as calcium mobilization and integrin activation in response to CRP or rhodocytin (CLEC-2 agonist) alone, were significantly diminished in groups A and B. At the same time, platelet responses to ADP with or without TRAP-6 were unaltered. Thrombi formation from collagen in parallel plate flow chambers was also noticeably decreased in groups A and B. In silico analysis of these results predicted diminished amounts of CLEC-2 on the platelet surface of patients, which was further confirmed by immunofluorescence microscopy and flow cytometry. In addition, we also noted a decrease in GPVI levels on platelets from group A. In KHE/KMP, platelet responses induced by CLEC-2 or GPVI activation are impaired because of the diminished number of receptors on the platelet surface. This impairment correlates with the severity of the disease and resolves as the patient recovers.
Assuntos
Hemangioendotelioma , Síndrome de Kasabach-Merritt , Sarcoma de Kaposi , Humanos , Criança , Síndrome de Kasabach-Merritt/diagnóstico , Síndrome de Kasabach-Merritt/complicações , Síndrome de Kasabach-Merritt/terapia , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/complicações , Hemangioendotelioma/terapia , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/terapia , Lectinas Tipo CRESUMO
Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1 , Neoplasias Hepáticas/tratamento farmacológico , Imunoterapia , Biomarcadores , Biomarcadores TumoraisRESUMO
BACKGROUND & AIMS: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood. METHODS: We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas. RESULTS: There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells. CONCLUSIONS: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.
Assuntos
Adenocarcinoma , Adenoma , Neoplasias do Colo , Neoplasias Colorretais , Animais , Humanos , Camundongos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenoma/genética , Adenoma/patologia , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Epigênese Genética , Oxigenases de Função Mista/genética , Fenótipo , Proteínas Proto-Oncogênicas/genéticaRESUMO
Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. SIGNIFICANCE: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Interleucina-27 , Neoplasias Hepáticas , Linfócitos T Citotóxicos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interleucina-27/imunologia , Interleucinas/imunologia , Neoplasias Hepáticas/imunologia , Prognóstico , Receptores de Interleucina/imunologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologiaRESUMO
Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).
Assuntos
Linfócitos B/patologia , Linfócitos B/virologia , Neoplasias do Sistema Nervoso Central/virologia , Epigênese Genética , Infecções por Vírus Epstein-Barr/patologia , Animais , Linfócitos B/metabolismo , Transformação Celular Viral/fisiologia , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4 , Linfoma/metabolismo , Linfoma/patologia , Linfoma/virologia , Camundongos , Osteopontina/metabolismoRESUMO
Atherosclerosis is a lipid-driven chronic inflammatory disease that is characterized by the formation and progressive growth of atherosclerotic plaques in the wall of arteries. Atherosclerosis is a major predisposing factor for stroke and heart attack. Various immune-mediated mechanisms are implicated in the disease initiation and progression. Cytokines are key mediators of the crosstalk between innate and adaptive immune cells as well as non-hematopoietic cells in the aortic wall and are emerging players in the regulation of atherosclerosis. Progression of atherosclerosis is always associated with increased local and systemic levels of pro-inflammatory cytokines. The role of cytokines within atherosclerotic plaque has been extensively investigated; however, the cell-specific role of cytokine signaling, particularly the role of cytokines in the regulation of barrier tissues tightly associated with microbiota in the context of cardiovascular diseases has only recently come to light. Here, we summarize the knowledge about the function of cytokines at mucosal barriers and the interplay between cytokines, barriers, and microbiota and discuss their known and potential implications for atherosclerosis development.
Assuntos
Aterosclerose/microbiologia , Citocinas/metabolismo , Microbiota , Mucosa/patologia , Animais , Aterosclerose/patologia , Interações Hospedeiro-Patógeno , Humanos , Inflamação/patologiaRESUMO
In this work, we present a new method-Thrombodynamics-4D-for the assessment of both plasma and platelet contributions to clotting. Thrombodynamics-4D potentially allows for the determination of plasma or platelet disorders and the effects of various drugs on plasma clotting or on platelet procoagulant function. In this assay, clot formation in platelet-rich plasma or platelet-free plasma supplemented with phospholipids is activated with tissue factor immobilized on a surface. Spatial fibrin clot growth and thrombin concentration dynamics are registered by measuring light scattering of the fibrin clot and fluorescence of the product formed by cleavage of the synthetic fluorogenic substrate by thrombin, respectively. Here, we describe the preanalytical requirements, measurement methodology and calculation principles of assay parameters. Preanalytical and analytical variability and reference ranges of the assay are given. Additionally, we show some clinical examples, which determine the effect of anticoagulants, measure clotting dysfunction in patients with platelet or coagulation disorders and evaluate the effect of surgery.
Assuntos
Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/fisiologia , Fibrina/metabolismo , Fosfolipídeos/metabolismo , Trombina/metabolismo , HumanosRESUMO
Abdominal aortic aneurysm (AAA) is a prevalent life-threatening disease, where aortic wall degradation is mediated by accumulated immune cells. Although cytokines regulate inflammation within the aorta, their contribution to AAA via distant alterations, particularly in the control of hematopoietic stem cell (HSC) differentiation, remains poorly defined. Here we report a pathogenic role for the interleukin-27 receptor (IL-27R) in AAA, as genetic ablation of IL-27R protects mice from the disease development. Mitigation of AAA is associated with a blunted accumulation of myeloid cells in the aorta due to the attenuation of Angiotensin II (Ang II)-induced HSC expansion. IL-27R signaling is required to induce transcriptional programming to overcome HSC quiescence and increase differentiation and output of mature myeloid cells in response to stress stimuli to promote their accumulation in the diseased aorta. Overall, our studies illuminate how a prominent vascular disease can be distantly driven by a cytokine-dependent regulation of bone marrow precursors.
Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Interleucina-27/metabolismo , Mielopoese/fisiologia , Receptores de Interleucina/metabolismo , Aneurisma/metabolismo , Angiotensina II/metabolismo , Animais , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Pressão Sanguínea , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Células Mieloides/patologia , Receptores de Interleucina/genética , Transdução de SinaisRESUMO
Cardiovascular diseases (CVD) are the major cause of death in developed countries. Various risk factors including host genetics and, more importantly, environmental factors such as lifestyle, diet and smoking influence CVD progression. Two common forms of CVD are atherosclerosis and abdominal aortic aneurysm (AAA). Emerging evidence suggests that inflammation plays a pivotal role in CVD. However, it remains unclear whether the same inflammatory pathways prove essential for atherosclerosis and AAA because, in some cases, the same mechanisms uniformly promote both diseases, while in others they function in opposite ways. Cytokines, key mediators of inflammation, play an important role in the development of atherosclerosis but have only been scarcely studied in AAA. In this review, we discuss the importance of immune-mediated mechanisms and cytokines in the pathogenesis of atherosclerosis and AAA.
Assuntos
Angiotensina II/genética , Aneurisma da Aorta Abdominal/genética , Aterosclerose/genética , Citocinas/genética , Angiotensina II/imunologia , Animais , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/patologia , Citocinas/imunologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Fatores de Risco , Comportamento Sedentário , Fumar/efeitos adversos , Fumar/fisiopatologiaRESUMO
Chronic inflammation and associated pathways are significant facilitators of many disease states, including malignancies. In the context of cancer, fibroblasts can actively regulate both inflammation and carcinogenesis. In this issue, Hamilton and colleagues describe a fibroblast-specific role of the RNA binding protein Imp1 in suppression of intestinal inflammatory responses and development of colitis-associated cancer.
Assuntos
Proteínas de Ligação a RNA/metabolismo , Microambiente Tumoral , Animais , HumanosRESUMO
Cytokines can provide survival and proliferation signals to cancer cells, thus promoting tumor progression. In this issue of Immunity, Kryczek et al. (2014) reveal that interleukin-22 can also promote "stemness" in human colorectal cancer via transcription factor STAT3-mediated epigenetic regulation of stem cell genes.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias Colorretais/imunologia , Interleucinas/imunologia , Metiltransferases/imunologia , Células-Tronco Neoplásicas/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Histona-Lisina N-Metiltransferase , Humanos , Interleucina 22RESUMO
RATIONALE: Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown. OBJECTIVE: The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development. METHODS AND RESULTS: Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas. CONCLUSIONS: The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
Assuntos
Aterosclerose/imunologia , Aterosclerose/metabolismo , Interleucinas/metabolismo , Receptores de Citocinas/metabolismo , Receptores de LDL/genética , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo , Aorta/citologia , Aorta/imunologia , Aorta/metabolismo , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Quimiocina CCL2/metabolismo , Feminino , Interleucina-17/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Interleucina , Receptores de LDL/metabolismo , Transdução de Sinais/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries characterized by leukocyte accumulation in the vessel wall. Both innate and adaptive immune responses contribute to atherogenesis, but the identity of atherosclerosis-relevant antigens and the role of antigen presentation in this disease remain poorly characterized. We developed live-cell imaging of explanted aortas to compare the behavior and role of APCs in normal and atherosclerotic mice. We found that CD4+ T cells were capable of interacting with fluorescently labeled (CD11c-YFP+) APCs in the aortic wall in the presence, but not the absence, of cognate antigen. In atherosclerosis-prone Apoe-/-CD11c-YFP+ mice, APCs extensively interacted with CD4+ T cells in the aorta, leading to cell activation and proliferation as well as secretion of IFN-γ and TNF-α. These cytokines enhanced uptake of oxidized and minimally modified LDL by macrophages. We conclude that antigen presentation by APCs to CD4+ T cells in the arterial wall causes local T cell activation and production of proinflammatory cytokines, which promote atherosclerosis by maintaining chronic inflammation and inducing foam cell formation.
Assuntos
Células Apresentadoras de Antígenos/metabolismo , Aterosclerose/patologia , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular , Vasculite/patologia , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/fisiologia , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/imunologia , Antígenos CD11/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Rastreamento de Células , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/fisiologia , Dieta Hiperlipídica , Feminino , Antígenos Comuns de Leucócito/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia , Técnicas de Cultura de Tecidos , Vasculite/imunologiaRESUMO
OBJECTIVES: This study tested whether immunosuppression with mycophenolate mofetil (MMF) inhibits atherosclerosis development in apolipoprotein-E-deficient (Apoe(-/-)) mice and investigated the mechanism. BACKGROUND: Chronic vascular inflammation involving both innate and adaptive immunity is central in the development of atherosclerosis, but immunosuppressive treatment is not uniformly beneficial. The immunosuppressive MMF targets lymphocyte proliferation by inhibiting inosine-monophosphate dehydrogenase. METHODS: Young and aged Apoe(-/-) mice were treated with 30 mg/kg daily MMF during 12 and 3 weeks of a high-fat diet, respectively. Aortic lesion size and composition was investigated by histology and flow cytometry; soluble inflammatory mediators were investigated by enzyme-linked immunosorbent assay. RESULTS: Macroscopic and histologic aortic atherosclerotic lesions were significantly decreased in both MMF-treated groups. While systemic immunoglobulin G directed against low-density lipoproteins was not significantly altered, the T-cell cytokine interleukin (IL)-17 was significantly reduced in plasma of MMF-treated mice and supernatants from their aortas after T-cell stimulation. The MMF treatment decreased aortic αß T-cell receptor(+) lymphocyte proliferation and cell numbers. Also, aortic contents of CD11b(+)CD11c(+) cells and their proliferation were reduced in MMF-treated Apoe(-/-) mice. The IL-17 supplementation restored the number of proliferating aortic CD11b(+)CD11c(+) cells in MMF-treated mice. The IL-17 receptor A was highly expressed on circulating monocytes that are macrophage progenitors. Genetic deletion of IL-17 receptor A or IL-17A reduced inflammatory peritoneal CD11b(+)CD11c(+) macrophage accumulation. CONCLUSIONS: The lymphocyte-directed immunosuppressant MMF that curbs IL-17 production was a successful antiatherosclerotic treatment. Our data delineate a role for IL-17 in CD11b(+)CD11c(+) cell accumulation.
Assuntos
Doenças da Aorta/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Imunossupressores/uso terapêutico , Ácido Micofenólico/análogos & derivados , Animais , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteínas E , Aterosclerose/metabolismo , Aterosclerose/patologia , Feminino , Imunossupressores/farmacologia , Interleucina-17/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Linfócitos T/fisiologiaRESUMO
Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagen-producing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.