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1.
Haematologica ; 103(4): 728-737, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29326120

RESUMO

Previously, we found that LDL-receptor related protein-1 on macrophages mediated shear stress-dependent clearance of von Willebrand factor. In control experiments, however, we observed that von Willebrand factor also binds to macrophages independently of this receptor under static conditions, suggesting the existence of additional clearance-receptors. In search for such receptors, we focused on the macrophage-specific scavenger-receptor SR-AI. von Willebrand factor displays efficient binding to SR-AI (half-maximum binding 14±5 nM). Binding is calcium-dependent and is inhibited by 72±4% in the combined presence of antibodies against the A1- and D4-domains. Association with SR-AI was confirmed in cell-binding experiments. In addition, binding to bone marrow-derived murine SR-AI-deficient macrophages was strongly reduced compared to binding to wild-type murine macrophages. Following expression via hydrodynamic gene transfer, we determined ratios for von Willebrand factor-propeptide over von Willebrand factor-antigen, a marker of von Willebrand factor clearance. Propeptide/antigen ratios were significantly reduced in SR-AI-deficient mice compared to wild-type mice (0.6±0.2 versus 1.3±0.3; P<0.0001), compatible with a slower clearance of von Willebrand factor in SR-AI-deficient mice. Interestingly, mutants associated with increased clearance (von Willebrand factor/p.R1205H and von Willebrand factor/p.S2179F) had significantly increased binding to purified SR-AI and SR-AI expressed on macrophages. Accordingly, propeptide/antigen ratios for these mutants were reduced in SR-AI-deficient mice. In conclusion, we have identified SR-AI as a novel macrophage-specific receptor for von Willebrand factor. Enhanced binding of von Willebrand factor mutants to SR-AI may contribute to the increased clearance of these mutants.


Assuntos
Receptores Depuradores Classe A/fisiologia , Fator de von Willebrand/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Macrófagos , Camundongos , Proteínas Mutantes/metabolismo , Ligação Proteica , Receptores Depuradores/fisiologia , Fator de von Willebrand/genética
2.
J Hepatol ; 68(4): 733-743, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29154963

RESUMO

BACKGROUND & AIMS: The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, which plays an important role in the maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 in FH pathogenesis. METHODS: Msr1-deficient (Msr1-/-) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion. RESULTS: Our results showed that Msr1-/- mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type and Msr1-/- mice, suggesting that C5a-induced pro-inflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal-regulated kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection. CONCLUSIONS: Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and subsequent complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH. LAY SUMMARY: Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH.


Assuntos
Ativação do Complemento , Hepatite Viral Animal/etiologia , Neutrófilos/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Complemento C5a/biossíntese , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/terapia , Humanos , MAP Quinase Quinase Quinases/fisiologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Vírus da Hepatite Murina , Receptores Depuradores Classe A/antagonistas & inibidores
3.
Neuromolecular Med ; 19(4): 463-479, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28828577

RESUMO

In this study, we investigated the uptake of malondialdehyde (MDA)-modified myelin oligodendrocyte glycoprotein (MOG) in the context of lipid peroxidation and its implications in CNS autoimmunity. The use of custom-produced fluorescently labeled versions of MOG or MDA-modified MOG enabled us to study and quantify the uptake by different macrophage populations and to identify the responsible receptor, namely SRA. The SRA-mediated uptake of MDA-modified MOG is roughly tenfold more efficient compared to that of the native form. Notably, this uptake is most strongly associated with anti-inflammatory M2-type macrophages. MDA-modified MOG was demonstrated to be resistant to degradation by lysine-dependent proteases in vitro, but the overall digestion fragments appeared to be similar in cell lysates, although their relative abundance appeared to be altered as a result of faster uptake. Accordingly, MDA-modified MOG is processed for presentation by APCs, allowing maximized recall proliferation of MOG35-55-specific 2D2 T cells in vitro due to higher uptake. However, MDA modification of MOG did not enhance immune priming or disease course in the in vivo MOG-EAE model, but did induce antibody responses to both MOG and MDA adducts. Taken together our results indicate that MDA adducts primarily constitute clearance signals for phagocytes and promote rapid removal of antigen, which is subjected to immunological screening by previously licensed T cells.


Assuntos
Autoantígenos/imunologia , Peroxidação de Lipídeos , Macrófagos/imunologia , Malondialdeído/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Receptores Depuradores Classe A/fisiologia , Animais , Autoantígenos/metabolismo , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Inflamação , Ativação Linfocitária , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Peptídeo Hidrolases/metabolismo , Proteólise , Células RAW 264.7 , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Linfócitos T/imunologia
4.
J Immunol ; 198(10): 3775-3789, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28483986

RESUMO

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.


Assuntos
Receptores Depuradores/classificação , Receptores Depuradores/fisiologia , Animais , Endocitose , Humanos , Ligantes , Camundongos , National Institute of Allergy and Infectious Diseases (U.S.)/normas , Fagocitose , Receptores Imunológicos/fisiologia , Receptores Depuradores Classe A/fisiologia , Transdução de Sinais , Terminologia como Assunto , Estados Unidos
5.
Cancer Res ; 77(7): 1586-1598, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28202524

RESUMO

Mechanisms of cross-talk between tumor cells and tumor-associated macrophages (TAM), which drive metastasis, are not fully understood. Scavenger receptor A1 (SR-A1) expressed primarily in macrophages has been associated with lung tumorigenesis. In this study, we used population genetics, transcriptomics, and functional analyses to uncover how SR-A1 is involved in lung cancer and its prognosis. SR-A1 genetic variants were investigated for possible association with survival of advanced stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were associated significantly with poor overall survival in this cohort. Data from The Cancer Genome Atlas showed considerable downregulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from mice genetically deficient for SR-A1 exhibited accelerated metastasis in a model of lung cancer. On the other hand, tumor cell seeding, migration, and invasion, as well as macrophage accumulation in lung cancer tissue, were enhanced in SR-A1-deficient mice. SR-A1 deletion upregulated serum amyloid A1 (SAA1) in macrophages via MAPK/IκB/NFκB signaling. SAA1 promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. Overall, our findings show how SR-A1 suppresses lung cancer metastasis by downregulating SAA1 production in TAMs. Cancer Res; 77(7); 1586-98. ©2017 AACR.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Macrófagos/fisiologia , Metástase Neoplásica/prevenção & controle , Receptores Depuradores Classe A/fisiologia , Proteína Amiloide A Sérica/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Movimento Celular , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Camundongos , Invasividade Neoplásica , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores Depuradores Classe A/genética , Microambiente Tumoral
6.
Blood ; 127(6): 778-86, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26608330

RESUMO

Beside its classical role in the coagulation cascade, coagulation factor X (FX) is involved in several major biological processes including inflammation and enhancement of virus-induced immune responses. We recently reported that the long circulatory half-life of FX is linked to its interaction with liver-resident macrophages. Importantly, we now observed that macrophages, but not undifferentiated monocytes, support this interaction. Using cell biology approaches with primary and THP1-derived macrophages as well as transfected cells, we further identified the scavenger receptor type A member I (SR-AI) to be a macrophage-specific receptor for FX. This result was confirmed using SR-AI-deficient mice, which exhibit reduced circulating levels of FX in vivo and loss of FX-macrophage interactions in vitro. Binding studies using purified proteins revealed that FX binds specifically (half-maximal binding, 3 µg/mL) to the extracellular domain of SR-AI. Altogether, we demonstrate that macrophages regulate FX plasma levels in an SR-AI-dependent manner.


Assuntos
Fator X/metabolismo , Receptores Depuradores Classe A/fisiologia , Animais , Coagulação Sanguínea/genética , Diferenciação Celular/genética , Células Cultivadas , Células HEK293 , Humanos , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Monócitos/fisiologia , Receptores Depuradores Classe A/genética
7.
Am J Physiol Endocrinol Metab ; 307(12): E1153-65, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25352436

RESUMO

In response to hyperglycemia in patients with diabetes, many signaling pathways contribute to the pathogenesis of diabetic complications, including diabetic retinopathy (DR). Excessive production of inflammatory mediators plays an important role in this process. Amadori-glycated albumin, one of the major forms of advanced glycated end-products, has been implicated in DR by inducing inflammatory responses in microglia/macrophages. Our goal was to delineate the potential cross talk between class A scavenger receptor (SR-A) and the receptor for advanced glycated end-product (RAGE) in the context of DR. We show here that SR-A ablation caused an exacerbated form of DR in streptozotocin-injected C57BL/6J mice as evidenced by fundus imaging and electroretinography. Immunohistochemical staining and RT-PCR assay indicated that there was augmented activation of proinflammatory macrophages with upregulated synthesis of proinflammatory mediators in the retina in Sr-a(-/-) mice. Overexpression of SR-A suppressed RAGE-induced mitogen-activated protein kinase (MAPK) signaling, whereas RAGE activation in macrophages favored a proinflammatory (M1) phenotype in the absence of SR-A. Mechanistic analysis on bone marrow-derived macrophages and HEK293 cell line revealed that SR-A interacted with and inhibited the phosphorylation of mitogen-activated protein kinase kinase 7, the major kinase in the RAGE-MAPK-NF-κB signaling, thereby leading to diminished secretion of proinflammatory cytokines. Our findings suggest that the antagonism between SR-A and RAGE contributes to the pathogenesis of DR by nurturing a disease-prone macrophage phenotype. Therefore, specific agonist that boosts SR-A signaling could potentially provide benefits in the prevention and/or intervention of DR.


Assuntos
Retinopatia Diabética/genética , Receptor Cross-Talk/fisiologia , Receptores Imunológicos/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Células HEK293 , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais/genética , Estreptozocina
8.
PLoS One ; 9(4): e94197, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24718459

RESUMO

Beta-amyloid (Aß) aggregates have a pivotal role in pathological processing of Alzheimer's disease (AD). The clearance of Aß monomer or aggregates is a causal strategy for AD treatment. Microglia and astrocytes are the main macrophages that exert critical neuroprotective roles in the brain. They may effectively clear the toxic accumulation of Aß at the initial stage of AD, however, their functions are attenuated because of glial overactivation. In this study, we first showed that heptapeptide XD4 activates the class A scavenger receptor (SR-A) on the glia by increasing the binding of Aß to SR-A, thereby promoting glial phagocytosis of Aß oligomer in microglia and astrocytes and triggering intracellular mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, XD4 enhances the internalization of Aß monomers to microglia and astrocytes through macropinocytosis or SR-A-mediated phagocytosis. Furthermore, XD4 significantly inhibits Aß oligomer-induced cytotoxicity to glial cells and decreases the production of proinflammatory cytokines, such as TNF-α and IL-1ß, in vitro and in vivo. Our findings may provide a novel strategy for AD treatment by activating SR-A.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Microglia/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/farmacologia , Receptores Depuradores/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrocitoma/patologia , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Córtex Cerebral/citologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Interleucina-1beta/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Ratos , Fator de Necrose Tumoral alfa/metabolismo
9.
Innate Immun ; 20(8): 826-47, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24257313

RESUMO

SR-A/CD204 and CD36 are major receptors responsible for oxidized lipoproteins uptake by macrophages in atherosclerotic plaques. Both receptors also share the role as receptors for different pathogens, but studies on their signaling have been hampered by the lack of selective ligands. We report that, upon specific ligation by Ab, SR-A does not induce cytokine production, but mediates inhibition of LPS-stimulated production of IL-6 and IL-12/23p40, enhancement of IL-10 release, and has no effect on TNF-α and RANTES production in murine macrophages. In contrast, anti-CD36 Ab alone stimulated production of all these cytokines, with IL-10 production being exceptionally high. Effects of anti-CD36 Ab, except of IL-10 production, were mediated by CD14 and TLR2, whereas those of SR-A ligation by heterotrimeric Gi/o proteins and by phosphatidylinositol 3-kinases. Surprisingly, we found that LPS uptake by macrophages was mediated in part by CD36 cooperating with CD14, whereas SR-A was not involved in this process. Finely, during in vitro Ag presentation to naïve CD4(+) lymphocytes, pre-incubation of macrophages with anti-CD36 Ab enhanced IFN-γ production in the co-culture, but exerted the opposite effect under conditions enabling IL-10 accumulation. In contrast, anti-SR-A Ab was ineffective alone, but reversed the Th1-polarizing effect of LPS.


Assuntos
Antígenos CD36/fisiologia , Imunidade Celular/fisiologia , Macrófagos/imunologia , Macrófagos/fisiologia , Receptores Depuradores Classe A/fisiologia , Androstadienos/farmacologia , Animais , Antígenos CD36/genética , Células Cultivadas , Citocinas/biossíntese , Feminino , Receptores de Lipopolissacarídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Toxina Pertussis/farmacologia , Receptores Depuradores Classe A/genética , Receptor 2 Toll-Like/efeitos dos fármacos , Wortmanina
10.
J Leukoc Biol ; 94(5): 1025-36, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23911868

RESUMO

Poly I:C, a synthetic dsRNA analogue, has been used extensively for decades to study innate responses in vivo and in different cell types. We have found substantial variability while using poly I:C from different sources. In this study we found that poly I:C from 2 commercial sources induced sharply opposite responses in myeloid and fibroblasts, depending on the length of the poly I:C. Although short poly I:C (≈ 1-1.5 kb) induced greater amounts of TNF-α, IL-8, and IFN-ß and a stronger antiviral response in myeloid cells, it was a poor inducer in fibroblasts. By contrast, long poly I:C (>5 kb) preferentially elicited higher cytokine and antiviral responses in fibroblasts and showed diminished responses in myeloid cells. Poly I:C activated NF-κB and STAT-1 signaling in a length- and cell-type-dependent fashion. Mechanistically, short poly I:C was better internalized in the myeloid cells and long poly I:C in the fibroblasts. Finally, long poly I:C required SR-A, whereas short poly I:C required RIG-I and Raftlin. We provide evidence that the length of dsRNA drives distinct innate responses in different cell lineages. These findings may augment in selecting the appropriate poly I:C type to design cell-type-specific potent adjuvants for vaccines against infectious diseases or cancers.


Assuntos
Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Poli I-C/farmacologia , Animais , Células Cultivadas , Endocitose , Interferon Tipo I/biossíntese , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , NF-kappa B/fisiologia , Receptores Depuradores Classe A/fisiologia , Fator de Necrose Tumoral alfa/biossíntese
11.
Invest Ophthalmol Vis Sci ; 54(9): 5959-70, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23927892

RESUMO

PURPOSE: Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS: Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A(-/-)), MARCO (MARCO(-/-)), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS: Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1- and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice. CONCLUSIONS: The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.


Assuntos
Neovascularização de Coroide/metabolismo , Macrófagos/metabolismo , Receptores Depuradores/fisiologia , Receptores Depuradores Classe A/fisiologia , Animais , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Angiofluoresceinografia , Fundo de Olho , Imuno-Histoquímica , Lasers/efeitos adversos , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica
12.
J Immunol ; 191(1): 238-48, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23733871

RESUMO

Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA(+/+) mice and SRA(-/-) mice were infected intratracheally with C. neoformans. Results show that infection of SRA(-/-) mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA(+/+) mice. Improved fungal clearance in SRA(-/-) mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4(+) T cells and CD11b(+) dendritic cells. Additional parameters were consistent with enhanced anticryptococcal immunity in the infected SRA(-/-) mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.


Assuntos
Criptococose/imunologia , Criptococose/patologia , Cryptococcus neoformans/imunologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/patologia , Receptores Depuradores Classe A/fisiologia , Animais , Células Cultivadas , Criptococose/microbiologia , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/patogenicidade , Feminino , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Pneumopatias Fúngicas/microbiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética
13.
Crit Rev Immunol ; 33(1): 57-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23627007

RESUMO

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.


Assuntos
Hepatopatias/etiologia , Receptores Depuradores/fisiologia , Animais , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/fisiologia , Antígenos CD36/fisiologia , Antígenos CD5/fisiologia , Doença Crônica , Fígado Gorduroso/complicações , Hepatite B Crônica/etiologia , Hepatite C Crônica/etiologia , Humanos , Hepatopatias Alcoólicas/complicações , Neoplasias Hepáticas/etiologia , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/fisiologia , Hepatopatia Gordurosa não Alcoólica , Receptores de Superfície Celular/fisiologia , Receptores Depuradores Classe A/fisiologia , Receptores Depuradores Classe F/fisiologia
14.
Biochim Biophys Acta ; 1832(2): 336-46, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23123599

RESUMO

The macrophage scavenger receptor class A (SR-A) participates in the innate immune and inflammatory responses. This study examined the role of macrophage SR-A in myocardial ischemia/reperfusion (I/R) injury and hypoxia/reoxygenation (H/R)-induced cell damage. SR-A(-/-) and WT mice were subjected to ischemia (45min) followed by reperfusion for up to 7days. SR-A(-/-) mice showed smaller myocardial infarct size and better cardiac function than did WT I/R mice. SR-A deficiency attenuated I/R-induced myocardial apoptosis by preventing p53-mediated Bak-1 apoptotic signaling. The levels of microRNA-125b in SR-A(-/-) heart were significantly greater than in WT myocardium. SR-A is predominantly expressed on macrophages. To investigate the role of SR-A macrophages in H/R-induced injury, we isolated peritoneal macrophages from SR-A deficient (SR-A(-/-)) and wild type (WT) mice. Macrophages were subjected to hypoxia followed by reoxygenation. H/R markedly increased NF-κB binding activity as well as KC and MCP-1 production in WT macrophages but not in SR-A(-/-) macrophages. H/R induced caspase-3/7 and -8 activities and cell death in WT macrophages, but not in SR-A(-/-) macrophages. The levels of miR-125b in SR-A(-/-) macrophages were significantly higher than in WT macrophages. Transfection of WT macrophages with miR-125b mimics attenuated H/R-induced caspase-3/7 and -8 activities and H/R-decreased viability, and prevented H/R-increased p-53, Bak-1 and Bax expression. The data suggest that SR-A deficiency attenuates myocardial I/R injury by targeting p53-mediated apoptotic signaling. SR-A(-/-) macrophages contain high levels of miR-125b which may play a role in the protective effect of SR-A deficiency on myocardial I/R injury and H/R-induced cell damage.


Assuntos
Macrófagos/metabolismo , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Receptores Depuradores Classe A/fisiologia , Animais , Apoptose , Western Blotting , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptores Depuradores Classe A/genética
15.
J Immunol ; 189(8): 4024-39, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22988031

RESUMO

Scavenger receptors (SRs) play crucial roles in innate immunity by acting as pattern recognition receptors. Although SRs are widely documented in mammals, data on their occurrence and functions in ancient vertebrates are limited. In this study, we report, to our knowledge, the first cloning and functional characterization of an SR molecule from teleost fish (Tetraodon nigroviridis). This SR (TnSR) was identified as a homolog to mammalian scavenger receptor class A member 5 with the conserved structure of a class A SR. TnSR contained multidomains in a type II transmembrane receptor, including an SR cysteine-rich domain, two coiled-coil collagenous domains, a transmmebrane domain, and a short N-terminal intracellular region with an unexpected TNFR-associated factor 2-binding consensus motif similar to that in human MSR molecules. Phylogenetic analysis suggested that TnSR may be an ancient member of class A SRs resulting from the close relationship between scavenger receptor class A member 5 and macrophage SR in vertebrates associated with the subtle differences in TnSR structure. Subcellular localization analysis showed that TnSR was a cell membrane receptor with homotrimer forms involved in the recognition and internalization of LPS from surface membranes into lysosomes. Functionally, TnSR expression was dramatically induced by LPS stimulation. TnSR served as a negative regulator in LPS-induced NF-κB activation by the competitive recruitment of TNFR-associated factor 2 from the TNF-α signaling pathway. To our knowledge, this is the first report showing that SR plays an inhibitory role in LPS-elicited inflammation by cross-talking with the TNF-α inflammatory pathway. These findings contribute to a better understanding of the biological and evolutionary history of the SR family.


Assuntos
Proteínas da Fase Aguda/fisiologia , Proteínas de Transporte/fisiologia , Regulação para Baixo/imunologia , Glicoproteínas de Membrana/fisiologia , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/imunologia , Fator 2 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/fisiologia , Animais , Dados de Sequência Molecular , NF-kappa B/metabolismo , Transporte Proteico/imunologia , Receptores Depuradores Classe A/fisiologia , Homologia de Sequência de Aminoácidos , Fator 2 Associado a Receptor de TNF/fisiologia , Tetraodontiformes
16.
Am J Pathol ; 180(1): 61-72, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22079429

RESUMO

Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.


Assuntos
Infecções por Haemophilus/imunologia , Imunidade Inata/fisiologia , Lipopolissacarídeos/farmacologia , Elastase Pancreática/farmacologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Receptores Depuradores Classe A/fisiologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Linhagem Celular , Citocinas/metabolismo , Infecções por Haemophilus/fisiopatologia , Haemophilus influenzae/imunologia , Medidas de Volume Pulmonar , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Muco/metabolismo , Fagocitose/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/microbiologia
17.
Tuberculosis (Edinb) ; 91 Suppl 1: S69-74, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22088322

RESUMO

The present study tested the hypothesis that the scavenger receptor SR-A modulates granuloma formation in response to pulmonary infection with Mycobacterium tuberculosis (MTB). To test this hypothesis, we monitored survival and histopathology in WT and SR-A-deficient mice following aerosol infection with MTB Rv. SR-A-deficient (SR-A-/-) mice infected with MTB survived significantly longer than WT mice; the mean survival of SR-A-/- mice exceeded 430 days compared to 230 days for WT mice. Early granuloma formation was not impaired in SR-A-/- mice. The extended survival of SR-A-/- mice was associated with 13- and 3-fold higher number of CD4+ lymphocytes and antigen presenting cells in SR-A-/- lungs compared to WT mice 280 after infection. The histopathology of chronically infected SR-A-/- lungs, however, was marked by abundant cholesterol clefts in parenchymal lesions containing infection in multinucleated giant cells. The present study indicates SR-A as a candidate gene of the innate immune system influencing the chronic phase of M. tuberculosis infection.


Assuntos
Receptores Depuradores Classe A/fisiologia , Tuberculose Pulmonar/metabolismo , Animais , Contagem de Linfócito CD4 , Células Cultivadas , Colesterol/metabolismo , Doença Crônica , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Células Gigantes/patologia , Granuloma/microbiologia , Imunidade Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/isolamento & purificação , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/imunologia , Análise de Sobrevida , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
18.
Pharmacol Rev ; 63(4): 967-1000, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21880988

RESUMO

The scavenger receptor cysteine-rich (SRCR) superfamily of soluble or membrane-bound protein receptors is characterized by the presence of one or several repeats of an ancient and highly conserved protein module, the SRCR domain. This superfamily (SRCR-SF) has been in constant and progressive expansion, now up to more than 30 members. The study of these members is attracting growing interest, which parallels that in innate immunity. No unifying function has been described to date for the SRCR domains, this being the result of the limited knowledge still available on the physiology of most members of the SRCR-SF, but also of the sequence versatility of the SRCR domains. Indeed, involvement of SRCR-SF members in quite different functions, such as pathogen recognition, modulation of the immune response, epithelial homeostasis, stem cell biology, and tumor development, have all been described. This has brought to us new information, unveiling the possibility that targeting or supplementing SRCR-SF proteins could result in diagnostic and/or therapeutic benefit for a number of physiologic and pathologic states. Recent research has provided structural and functional insight into these proteins, facilitating the development of means to modulate the activity of SRCR-SF members. Indeed, some of these approaches are already in use, paving the way for a more comprehensive use of SRCR-SF members in the clinic. The present review will illustrate some available evidence on the potential of well known and new members of the SRCR-SF in this regard.


Assuntos
Terapia de Alvo Molecular , Receptores Depuradores/fisiologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação Mielomonocítica/fisiologia , Humanos , Receptores de Superfície Celular/fisiologia , Receptores Imunológicos/fisiologia , Receptores Depuradores Classe A/fisiologia , Receptores Depuradores Classe B/fisiologia
19.
Blood ; 118(2): 390-400, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21596859

RESUMO

We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5(-/-) LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5(-/-) LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and ß-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Células-Tronco Neoplásicas/metabolismo , Receptores Depuradores Classe A/fisiologia , Animais , Araquidonato 5-Lipoxigenase/genética , Células Cultivadas , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/fisiologia , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Transplante Heterólogo
20.
Atherosclerosis ; 215(1): 60-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21215400

RESUMO

OBJECTIVE: Lipid rafts are cholesterol-enriched microdomains on cell membranes. We hypothesized that these microdomains could involve modified low-density lipoprotein (LDL) uptake. METHODS AND RESULTS: Co-localizations of cholesterol-enriched microdomains and CD204 during the uptake of acetyl LDL (AcLDL) and oxidized LDL were observed using Alexa488-labeled polyethylene glycol cholesteryl ester, which is a sensitive probe used to analyze the dynamics of cholesterol-rich lipid microdomains in living cells. The lipid raft disruptors, methyl-ß cyclodextrin and filipin, inhibited the uptake of AcLDL. CD204 siRNA treatments significantly reduced AcLDL uptake by 80%. We also demonstrated the presence of CD204 in the detergent-resistant membrane fraction (DRM) by immunoblotting analysis. The ratio of CD204/flotillin-1 in DRM was increased 11.5-fold by modified LDL administration. The PI3 kinase inhibitor LY294002, but not the Src kinase inhibitor PP1 or the Gαi/o inhibitor pertussis toxin, inhibited modified LDL uptake. The production of interleukin (IL)-8, but not CCL2, CXCL2, CXCL3, IL-6 or tumor necrosis factor-α was increased by AcLDL administration. The AcLDL-induced IL-8 production was inhibited by LY294002 and filipin. CONCLUSIONS: These data firstly demonstrated that PI3 kinase-associated cholesterol-enriched microdomains are involved in CD204-mediated modified LDL uptake in human macrophages. Cholesterol-enriched microdomains may play a critical role in inflammatory processes.


Assuntos
Macrófagos/metabolismo , Microdomínios da Membrana/metabolismo , Receptores Depuradores Classe A/metabolismo , Adulto , Células Cultivadas , Filipina/farmacologia , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Microdomínios da Membrana/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Receptores Depuradores Classe A/fisiologia , Transdução de Sinais/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia
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