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1.
Cell Immunol ; 372: 104483, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35085880

RESUMO

The occurring in SR-A/CD204- or CD36-deficient mice increased susceptibility to infections with Staphylococcus aureus (Sa) had traditionally been ascribed to the impairment of macrophage-mediated phagocytosis, which is, however, inconsistent with low effectiveness of unopsonized Sa killing within macrophages and redundant roles of both receptors in this process. We have found that Sa-stimulated cytokine production in mouse macrophages seems to be exclusively mediated by TLR2, mainly from within endosomes in response to Sa-derived lipoteichoic acid. By driving endocytic trafficking of TLR2 and its ligands through the clathrin-dependent pathway, CD36 and SR-A sensitize macrophages to activation by Sa as well as regulate the type and amount of cytokines produced. Additionally, upon direct Sa binding, both receptors autonomously generate anti-inflammatory signaling. Consequently, the delayed induction of acute inflammation in knockout mice may allow for the initial, uncontrolled multiplication of bacteria, stimulating excessive, septic shock-inducing production of inflammatory cytokines in later stages of infection.


Assuntos
Antígenos CD36/imunologia , Citocinas/biossíntese , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Receptores Depuradores Classe A/imunologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Endocitose/imunologia , Ligantes , Receptores de Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Reconhecimento de Padrão/imunologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia
2.
Circ Res ; 127(5): 610-627, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32466726

RESUMO

RATIONALE: Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. OBJECTIVE: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. METHODS AND RESULTS: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a proinflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of SR-A1 (class A1 scavenger receptor) inhibited proliferation of cardiac resident reparative macrophages and, therefore, exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc (Avian myelocytomatosis virus oncogene cellular homolog), a key transcriptional factor for the SR-A1-P38-SIRT1 (Sirtuin 1) pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. CONCLUSIONS: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.


Assuntos
Cardiomiopatia Dilatada/enzimologia , Proliferação de Células , Autorrenovação Celular , Macrófagos/enzimologia , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Depuradores Classe A/metabolismo , Animais , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Cardiomiopatia Dilatada/induzido quimicamente , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Doxorrubicina , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Transdução de Sinais , Remodelação Ventricular
3.
Am J Physiol Cell Physiol ; 321(3): C607-C614, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34378992

RESUMO

Bovine milk exosomes (BMEs) are being explored in drug delivery despite their rapid elimination by macrophages. We aimed at identifying the BME transporter in murine bone marrow-derived macrophages (BMDMs). Fluorophore-labeled BMEs were used in transport studies in BMDMs from C57BL/6J and class A scavenger receptor type 1/2 (CASR-1/2) knockout mice and tissue accumulation in macrophage-depleted C57BL/6J mice. Parametric and nonparametric statistics tests for pairwise and multiple comparisons were used. Chemical inhibitors of phagocytosis by cytochalasin D led to a 69 ± 18% decrease in BME uptake compared with controls (P < 0.05), whereas inhibitors of endocytic pathways other than phagocytosis had a modest effect on uptake (P > 0.05). Inhibitors of class A scavenger receptors (CASRs) including CASR-1/2 caused a 70% decrease in BME uptake (P < 0.05). The uptake of BMEs by BMDMs from CASR-1/2 knockout mice was smaller by 58 ± 23% compared with wild-type controls (P < 0.05). Macrophage depletion by clodronate caused a more than 44% decrease in BME uptake in the spleen and lungs (P < 0.05), whereas the decrease observed in liver was not statistically significant. In conclusion, CASR-1/2 facilitates the uptake of BMEs in BMDMs and C57BL/6J mice.


Assuntos
Exossomos/metabolismo , Macrófagos/metabolismo , Leite/química , Receptores Depuradores Classe A/genética , Animais , Bovinos , Ácido Clodrônico/farmacologia , Citocalasina D/farmacologia , Endocitose/efeitos dos fármacos , Exossomos/química , Feminino , Corantes Fluorescentes/química , Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Receptores Depuradores Classe A/deficiência , Baço/efeitos dos fármacos , Baço/metabolismo , Coloração e Rotulagem/métodos
4.
J Neuroinflammation ; 17(1): 62, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066456

RESUMO

BACKGROUND: A sustained inflammatory response following spinal cord injury (SCI) contributes to neuronal damage, inhibiting functional recovery. Macrophages, the major participants in the inflammatory response, transform into foamy macrophages after phagocytosing myelin debris, subsequently releasing inflammatory factors and amplifying the secondary injury. Here, we assessed the effect of macrophage scavenger receptor 1 (MSR1) in phagocytosis of myelin debris after SCI and explained its possible mechanism. METHODS: The SCI model was employed to determine the critical role of MSR1 in phagocytosis of myelin debris in vivo. The potential functions and mechanisms of MSR1 were explored using qPCR, western blotting, and immunofluorescence after treating macrophages and RAW264.7 with myelin debris in vitro. RESULTS: In this study, we found improved recovery from traumatic SCI in MSR1-knockout mice over that in MSR1 wild-type mice. Furthermore, MSR1 promoted the phagocytosis of myelin debris and the formation of foamy macrophage, leading to pro-inflammatory polarization in vitro and in vivo. Mechanistically, in the presence of myelin debris, MSR1-mediated NF-κB signaling pathway contributed to the release of inflammatory mediators and subsequently the apoptosis of neurons. CONCLUSIONS: Our study elucidates a previously unrecognized role of MSR1 in the pathophysiology of SCI and suggests that its inhibition may be a new treatment strategy for this traumatic condition.


Assuntos
Apoptose/fisiologia , Macrófagos/metabolismo , Neurônios/metabolismo , Receptores Depuradores Classe A/deficiência , Traumatismos da Medula Espinal/metabolismo , Animais , Células Cultivadas , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Células RAW 264.7 , Receptores Depuradores Classe A/genética , Traumatismos da Medula Espinal/patologia
5.
Blood ; 129(17): 2443-2454, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28213380

RESUMO

Recently, we have identified scavenger receptor class A member I (SR-AI) as a receptor for coagulation factor X (FX), mediating the formation of an FX reservoir at the macrophage surface. Here, we demonstrate that the FX/SR-AI-complex comprises a third protein, pentraxin-2 (PTX2). The presence of PTX2 is essential to prevent internalization of FX by SR-AI, and the presence of FX is needed to interfere with internalization of PTX2. Binding studies showed that FX, SR-AI, and PTX2 independently bind to each other (KD,app: 0.2-0.7 µM). Surprisingly, immunoprecipitation experiments revealed that FX and PTX2 circulate as a complex in plasma, and complex formation involves the FX activation peptide. No binding of PTX2 to other vitamin K-dependent proteins was observed. Short hairpin RNA-mediated inhibition of PTX2 levels in mice resulted not only in reduced levels of PTX2, but also in similarly reduced FX levels. Moreover, PTX2 and FX levels were correspondingly reduced in SR-AI-deficient mice. Analysis of 71 human plasma samples uncovered a strong correlation between FX and PTX2 plasma levels. Furthermore, plasma samples of patients with reduced FX levels (congenital/acquired FX deficiency or after anti-vitamin K treatment) were characterized by concomitantly decreased PTX2 levels. In conclusion, we identified PTX2 as a novel partner for FX, and both proteins cooperate to prevent their SR-AI-mediated uptake by macrophages. Interestingly, their respective plasma levels are interdependent. These findings seem of relevance in perspective of ongoing clinical trials, in which plasma depletion of PTX2 is used as a therapeutical approach in the management of systemic amyloidosis.


Assuntos
Proteína C-Reativa/metabolismo , Deficiência do Fator X/sangue , Fator X/metabolismo , Macrófagos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores Depuradores Classe A/metabolismo , Animais , Anticoagulantes/farmacologia , Proteína C-Reativa/genética , Linhagem Celular , Endocitose , Fator X/genética , Deficiência do Fator X/genética , Deficiência do Fator X/patologia , Expressão Gênica , Células HEK293 , Humanos , Cinética , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Depuradores Classe A/antagonistas & inibidores , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Vitamina K/antagonistas & inibidores , Vitamina K/metabolismo
6.
Cell Physiol Biochem ; 41(6): 2461-2474, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28472786

RESUMO

OBJECTIVE: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)-mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. METHODS: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-ß, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. RESULTS: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-ß, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-ß, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). CONCLUSION: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats.


Assuntos
Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sulfeto de Hidrogênio/toxicidade , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Creatina/sangue , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Rim/ultraestrutura , Masculino , Malondialdeído/análise , Malondialdeído/metabolismo , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Superóxido Dismutase/análise , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
7.
Arterioscler Thromb Vasc Biol ; 34(2): 365-76, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24233489

RESUMO

OBJECTIVE: The risk of cardiovascular disease is increased by up to 33 to 50× in chronic inflammatory states and convention doses of statins may not provide the same cardiovascular protection as in noninflamed patients. This study investigated whether the increase in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R)-mediated cholesterol synthesis observed under inflammatory stress was resistant to the action of statins and if so, whether this was because of interference with the sterol regulatory element binding protein cleavage-activating protein pathway. APPROACH AND RESULTS: Inflammatory stress was induced by adding cytokines (interleukin-1ß, tumor necrosis factor-α, and interleukin-6) and lipopolysaccharides to vascular smooth muscle cells in vitro and by subcutaneous casein injection in apolipoprotein E/scavenger receptors class A/CD36 triple knockout mice in vivo. Inflammatory stress exacerbated cholesterol ester accumulation and was accompanied in vitro and in vivo by increased HMGCoA-R mRNA and protein expression mediated via activation of the sterol regulatory element binding protein cleavage-activating protein/sterol regulatory element binding protein-2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro. However, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 16 µmol/L inhibited HMGCoA-R activity by 50% in vascular smooth muscle cells, but the same concentration resulted in only 30% of HMGCoA-R activity in vascular smooth muscle cells in the presence of interleukin-1ß. Knocking down sterol regulatory element binding protein cleavage-activating protein prevented statin resistance induced by interleukin-1ß, and overexpression of sterol regulatory element binding protein cleavage-activating protein induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease aortic lipid accumulation rose from 2 to 10 mg/kg per day in the presence of inflammatory stress. CONCLUSIONS: Increased cholesterol synthesis mediated by HMGCoA-R under inflammatory stress may be one of the mechanisms for intracellular lipid accumulation and statin resistance.


Assuntos
Resistência a Medicamentos , Ácidos Heptanoicos/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipidemias/tratamento farmacológico , Inflamação/enzimologia , Músculo Liso Vascular/efeitos dos fármacos , Pirróis/farmacologia , Estresse Fisiológico , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Atorvastatina , Antígenos CD36/deficiência , Antígenos CD36/genética , Colesterol/sangue , Colesterol na Dieta , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Retroalimentação Fisiológica , Células Hep G2 , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/enzimologia , Hiperlipidemias/genética , Inflamação/sangue , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Interferência de RNA , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Fatores de Tempo , Transfecção
8.
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
9.
J Immunol ; 190(7): 3798-805, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23447685

RESUMO

Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate that coculture of tumor-associated macrophages and tumor cells induces secretion of factors that are recognized by SR-A on tumor-associated macrophages. We tentatively identified several potential ligands for the SR-A receptor in tumor cell-macrophage cocultures by mass spectrometry. Competing with the coculture-induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumor cell invasion. In line with our in vitro findings, tumor progression and metastasis are inhibited in SR-A(-/-) mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumor-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumor progression and metastasis observed in SR-A(-/-) mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression.


Assuntos
Macrófagos/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Receptores Depuradores Classe A/genética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Knockout , Invasividade Neoplásica/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polieletrólitos , Polímeros/metabolismo , Ligação Proteica , Receptores Depuradores Classe A/antagonistas & inibidores , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/metabolismo , Carga Tumoral/efeitos dos fármacos
10.
PLoS Pathog ; 8(10): e1002967, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23071440

RESUMO

Sepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest that SRA acts as a pattern recognition receptor in the innate immune response. The goal of the present study was to determine the role of SRA in polymicrobial sepsis. SRA deficient (SRA(-/-)) and C57BL/6JB/6J (WT) male mice were subjected to cecal ligation and puncture (CLP) to induce polymicrobial sepsis. NFκB activity, myeloperoxidase activity, and co-association of SRA with toll like receptor (TLR) 4 and TLR2 was analyzed in the lungs. Spleens were analyzed for apoptosis. Serum cytokines and chemokines were assayed. Blood and peritoneal fluid were cultured for aerobic and anaerobic bacterial burdens. Long-term survival was significantly increased in SRA(-/-) septic mice (53.6% vs. 3.6%, p < 0.05) when compared to WT mice. NFκB activity was 45.5% lower in the lungs of SRA(-/-) septic mice versus WT septic mice (p < 0.05). Serum levels of interleukin (IL)-5, IL-6, IL-10 and monocyte chemoattractant protein -1 were significantly lower in septic SRA(-/-) mice when compared to septic WT mice (p < 0.05). We found that SRA immuno-precipitated with TLR4, but not TLR2, in the lungs of WT septic mice. We also found that septic SRA(-/-) mice had lower bacterial burdens than WT septic mice. SRA deficiency had no effect on pulmonary neutrophil infiltration or splenocyte apoptosis during sepsis. We conclude that SRA plays a pivotal, and previously unknown, role in mediating the pathophysiology of sepsis/septic shock in a murine model of polymicrobial sepsis. Mechanistically, SRA interacts with TLR4 to enhance the development of the pro-inflammatory phenotype and mediate the morbidity and mortality of sepsis/septic shock.


Assuntos
Coinfecção/imunologia , Receptores Depuradores Classe A/metabolismo , Sepse/imunologia , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Líquido Ascítico/microbiologia , Carga Bacteriana , Sangue/microbiologia , Ceco/cirurgia , Quimiocinas/sangue , Quimiocinas/imunologia , Coinfecção/microbiologia , Coinfecção/mortalidade , Citocinas/sangue , Citocinas/imunologia , Regulação da Expressão Gênica , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Infiltração de Neutrófilos , Peroxidase , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Sepse/microbiologia , Sepse/mortalidade , Choque Séptico/microbiologia , Baço/imunologia , Baço/metabolismo , Receptor 2 Toll-Like/metabolismo
11.
Am J Pathol ; 182(5): 1681-95, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23499552

RESUMO

Scavenger receptor A5 (SCARA5) is a member of the class A scavenger receptors, with most similarity to SCARA1 (SR-A) and SCARA2 (MARCO), which are primarily expressed by macrophages and dendritic cells, in which they participate in clearance of various polyanionic macromolecules, pollution particles, and pathogens. The biological role of SCARA5 has been unknown. Herein, we show that SCARA5 is an endocytotic receptor whose ligand repertoire includes the typical scavenger receptor ligands, whole bacteria, and purified Gram-negative bacterial lipopolysaccharide. In contrast to expression of SCARA1 and SCARA2 in immune cells, SCARA5 is found in a subset of fibroblast-like cells in the interstitial stroma of most organs, with additional expression in the epithelial cells of testis and choroid plexus. SCARA5-null mice develop with age lymphoid cell accumulation in many organs, in particular the lungs, and show decreased endocytotic function in fibroblasts. Furthermore, about one-third of the mice develop antinuclear antibodies. These disturbances are reminiscent of those found in many human autoimmune connective tissue disorders, which suggests that defects in fibroblast SCARA5 can underlie some forms of autoimmune disease.


Assuntos
Autoanticorpos/imunologia , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/patologia , Progressão da Doença , Tecido Linfoide/patologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Células CHO , Separação Celular , Doenças do Tecido Conjuntivo/sangue , Cricetinae , Cricetulus , Endocitose , Fibroblastos/metabolismo , Fibroblastos/patologia , Deleção de Genes , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microscopia Confocal , Dados de Sequência Molecular , Ligação Proteica , Transporte Proteico , Proteína A4 de Ligação a Cálcio da Família S100 , Proteínas S100/metabolismo , Receptores Depuradores Classe A/química , Células Estromais/metabolismo , Células Estromais/patologia
12.
Am J Respir Crit Care Med ; 186(8): 763-72, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22878280

RESUMO

RATIONALE: Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer. OBJECTIVES: To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis. METHODS: The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development. MEASUREMENTS AND MAIN RESULTS: The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function. CONCLUSIONS: Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.


Assuntos
Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Animais , Povo Asiático/genética , Carcinoma Pulmonar de Lewis , Estudos de Casos e Controles , China/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Knockout , Polimorfismo Genético
13.
Kidney Int ; 81(10): 1002-1014, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22377830

RESUMO

Scavenger receptor A (SR-A) is a key transmembrane receptor in the endocytosis of lipids and contributes to the pathogenesis of atherosclerosis. To assess its role in hyperlipidemic chronic kidney disease, wild-type and SR-A-deficient (knockout) mice underwent uninephrectomy followed by either normal or high-fat diet. After 16 weeks of diet intervention, hyperlipidemic wild-type mice presented characteristic features of progressive nephropathy: albuminuria, renal fibrosis, and overexpression of transforming growth factor (TGF)-ß1/Smad. These changes were markedly diminished in hyperlipidemic knockout mice and attributed to reduced renal lipid retention, oxidative stress, and CD11c(+) cell infiltration. In vitro, overexpression of SR-A augmented monocyte chemoattractant protein-1 release and TGF-ß1/Smad activation in HK-2 cells exposed to oxidized low-density lipoprotein. SR-A knockdown prevented lipid-induced cell injury. Moreover, wild-type to knockout bone marrow transplantation resulted in renal fibrosis in uninephrectomized mice following 16 weeks of the high-fat diet. In contrast, knockout to wild-type bone marrow transplantation led to markedly reduced albuminuria, CD11c(+) cell infiltration, and renal fibrosis compared to wild-type to SR-A knockout or wild-type to wild-type bone marrow transplanted mice, without difference in plasma lipid levels. Thus, SR-A on circulating leukocytes rather than resident renal cells predominantly mediates lipid-induced kidney injury.


Assuntos
Gorduras na Dieta/metabolismo , Hiperlipidemias/complicações , Nefropatias/prevenção & controle , Rim/metabolismo , Leucócitos/metabolismo , Receptores Depuradores Classe A/deficiência , Albuminúria/etiologia , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Transplante de Medula Óssea , Antígeno CD11c/metabolismo , Linhagem Celular , Quimiocina CCL2/metabolismo , Doença Crônica , Gorduras na Dieta/sangue , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hiperlipidemias/etiologia , Rim/patologia , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Knockout , Nefrectomia , Estresse Oxidativo , Interferência de RNA , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/metabolismo
14.
Immunol Cell Biol ; 90(1): 101-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21383767

RESUMO

Given the primary expression of scavenger receptor A (SRA) or CD204 on antigen-presenting cells, we investigate the immunoregulatory activities of SRA/CD204 in the context of cross-presentation of cell-associated antigen and the immunogenicity of dying tumor cells. Immunization with dying prostate cancer cells results in profoundly increased control of subsequently inoculated tumors in SRA/CD204 knockout mice. Using OVA-expressing RM1 prostate tumor line (RM1-OVA), we show for the first time that SRA absence greatly enhances dendritic cells (DCs)-mediated cross-presentation of OVA antigen derived from dying RM1 cells. While the phagocytic ability of DCs is not significantly impacted by the lack of SRA/CD204, DCs deficient in SRA/CD204 display increased expression of inflammatory cytokines and chemokines, as well as co-stimulatory molecules upon interaction with dying RM1 cells, implicating a suppressive regulation of the functional activation of DCs by SRA/CD204. Further, SRA/CD204-deficient DCs pulsed with dying RM1-OVA cells are more effective than wild-type counterparts in priming antigen-specific T-cell responses, resulting in improved control of RM1 tumor growth in both prophylactic and therapeutic settings. Our findings suggest that the increased immunogenicity of dying tumor cells in SRA/CD204 knockout mice is attributed to the altered functions of DCs in the absence of SRA/CD204, which underscores the important role of SRA/CD204 in host immune homeostasis. Selective downregulation or blockade of this immunoregulatory molecule may lead to enhanced potency of DC-based vaccines capable of breaking immune tolerance against cancer.


Assuntos
Antígenos/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Neoplasias Experimentais/imunologia , Receptores Depuradores Classe A/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/genética , Antígenos/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/transplante , Citometria de Fluxo , Imunoterapia Adotiva/métodos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Ovalbumina/genética , Ovalbumina/imunologia , Ovalbumina/metabolismo , Fagocitose/imunologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Carga Tumoral/genética , Carga Tumoral/imunologia
15.
J Neuroinflammation ; 9: 120, 2012 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-22676725

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by damage to the neuronal myelin sheath. One of the key effectors for inflammatory injury is the antigen-presenting cell (APC). The class A scavenger receptor (SRA), constitutively expressed by APCs, such as macrophages and dendritic cells in peripheral tissues and the CNS, was shown to play a role in the phagocytosis of myelin; however, the role of SRA in the development of experimental autoimmune encephalomyelitis (EAE) and autoimmune reaction in the periphery has not yet been studied. METHODS: We investigated EAE progression in wild-type (WT) vs. SRA-/- mice using clinical score measurements and characterized CNS pathology using staining. Furthermore, we assessed SRA role in mediating anti myelin pro-inflammatory response in cell cultures. RESULTS: We discovered that EAE progression and CNS demyelination were significantly reduced in SRA-/- mice compared to WT mice. In addition, there was a reduction of infiltrating peripheral immune cells, such as T cells and macrophages, in the CNS lesion of SRA-/- mice, which was associated with reduced astrogliosis. Immunological assessment showed that SRA deficiency resulted in significant reduction of pro-inflammatory cytokines that play a major role in EAE progression, such as IL-2, IFN-gamma, IL-17 and IL-6. Furthermore, we discovered that SRA-/- APCs showed impairments in activation and in their ability to induce pro-inflammatory CD4+ T cell proliferation. CONCLUSION: Expression of SRA on APCs is important for CD4+ T-cells proliferation in EAE mouse model. Further studies of SRA-mediated cellular pathways in APCs may offer useful insights into the development of MS and other autoimmune diseases, providing future avenues for therapeutic intervention.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Receptores Depuradores Classe A/biossíntese , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Progressão da Doença , Encefalomielite Autoimune Experimental/genética , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética
16.
Blood ; 113(23): 5819-28, 2009 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-19349620

RESUMO

Class A scavenger receptor (SRA), also known as CD204, has been shown to participate in the pathogenesis of atherosclerosis and the pattern recognition of pathogen infection. However, its role in adaptive immune responses has not been well defined. In this study, we report that the lack of SRA/CD204 promotes Toll-like receptor (TLR)4 agonist-augmented tumor-protective immunity, which is associated with enhanced activation of CD8(+) effector T cell and improved inhibition of tumor growth. Dendritic cells (DCs) deficient in SRA/CD204 display more effective immunostimulatory activities upon TLR4 engagement than those from wild-type counterparts. Silencing of SRA/CD204 by RNA interference improves the ability of DCs to prime antigen-specific CD8(+) T cells, suggesting that antigen-presenting cells, for example, DCs, play a major role in SRA/CD204-mediated immune modulation. Our findings reveal a previously unrecognized role for SRA/CD204, a non-TLR pattern recognition receptor, as a physiologic negative regulator of TLR4-mediated immune consequences, which has important clinical implications for development of TLR-targeted immunotherapeutic intervention.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação para Baixo/imunologia , Ativação Linfocitária/imunologia , Receptores Depuradores Classe A/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular , Proliferação de Células , Células Dendríticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Ovalbumina/imunologia , Interferência de RNA , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 29(1): 19-26, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18948635

RESUMO

OBJECTIVE: The scavenger receptors SR-A and CD36 have been implicated in macrophage foam cell formation during atherogenesis and in the regulation of inflammatory signaling pathways, including those leading to lesional macrophage apoptosis and plaque necrosis. To test the impact of deleting these receptors, we generated Apoe(-/-) mice lacking both SR-A and CD36 and fed them a Western diet for 12 weeks. METHODS AND RESULTS: We analyzed atheroma in mice, assessing lesion size, foam cell formation, inflammatory gene expression, apoptosis, and necrotic core formation. Aortic root atherosclerosis in Apoe(-/-)Cd36(-/-)Msr1(-/-) mice, as assessed by morphometry, electron microscopy, and immunohistochemistry, showed no decrease in lesion area or in vivo foam cell formation when compared to Apoe(-/-) mice. However, Apoe(-/-)Cd36(-/-)Msr1(-/-) lesions showed reduced expression of inflammatory genes and morphological analysis revealed a approximately 30% decrease in macrophage apoptosis and a striking approximately 50% decrease in plaque necrosis in aortic root lesions of these mice. CONCLUSIONS: Although targeted deletion of SR-A and CD36 does not abrogate macrophage foam cell formation or substantially reduce atherosclerotic lesion area in Apoe(-/-) mice, loss of these pathways does reduce progression to more advanced necrotic lesions. These data suggest that targeted inhibition of these pathways in vivo may reduce lesional inflammation and promote plaque stability.


Assuntos
Aterosclerose/patologia , Antígenos CD36/deficiência , Células Espumosas/patologia , Hiperlipidemias/fisiopatologia , Receptores Depuradores Classe A/deficiência , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Aterosclerose/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hiperlipidemias/genética , Inflamação/genética , Inflamação/fisiopatologia , Camundongos , Camundongos Knockout , RNA/genética , RNA/isolamento & purificação
18.
Biochemistry ; 48(50): 11858-71, 2009 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-19911804

RESUMO

Macrophage scavenger receptor A (SR-A) is a multifunctional, multiligand pattern recognition receptor with roles in innate immunity, apoptotic cell clearance, and age-related degenerative pathologies, such as atherosclerosis and Alzheimer's disease. Known endogenous SR-A ligands are polyanionic and include modified lipoproteins, advanced glycation end products, and extracellular matrix proteins. No native plasma ligands have been identified, but it is known that SR-A recognition of unidentified serum components mediates integrin-independent macrophage adhesion, which may drive chronic local inflammation. In this study, we used a high-throughput fractionation and screening method to identify novel endogenous SR-A ligands that may mediate macrophage adhesion. SR-A was found to recognize the exchangeable apolipoproteins A-I and E (apo A-I and apo E, respectively) in both lipid-free and lipid-associated form, suggesting the shared amphipathic alpha-helix as a potential recognition motif. Adhesion of RAW 264.7 macrophages to surfaces coated with apo A-I and apo E4 proved to be integrin-independent and could be blocked by anti-SR-A antibodies. The presence of apo A-I and apo E in pathological deposits, such as atherosclerotic lesions and neurotoxic Alzheimer's plaques, suggests a possible contribution of SR-A-dependent adhesion of macrophages to an inflammatory microenvironment.


Assuntos
Apolipoproteína A-I/metabolismo , Apolipoproteínas E/metabolismo , Macrófagos/metabolismo , Receptores Depuradores Classe A/fisiologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Apolipoproteína A-I/química , Apolipoproteínas E/química , Linhagem Celular , Humanos , Ligantes , Macrófagos/química , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Dados de Sequência Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Receptores Depuradores Classe A/química , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo
19.
Dig Dis Sci ; 54(12): 2561-7, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19117124

RESUMO

The multifunctional pattern recognition scavenger receptors, SR-A and CD36, are predominantly expressed by lamina propria macrophages and considered important in innate immunity. We examined the role of these receptors in the pathophysiology of inflammatory bowel disease. Colitis was induced in wild type (WT), SRA(-/-), CD36(-/-), and SR-A/CD36 double deficient mice by administering DSS. DSS-induced moderately severe colitis in WT mice was manifested by weight loss, reduced hematocrit, and pathology. SR-A/CD36 double deficient mice developed significantly more severe colitis as indicated by anemia (P<0.01), decreased colonic length due to inflammation (P<0.01), and lesions when compared with WT and single deficient animals. Serum amyloid A was significantly more elevated in SR-A/CD36(-/-) mice (P<0.01) compared with WT and single deficient animals. However, the spleens of WT mice (P<0.05) were significantly enlarged. Inflammatory cytokine levels were considerably increased in WT mice (IL-6 P<0.001, TNFα P<0.01). In contrast, SR-A deficient mice maintained more normal body and splenic weight and developed less severe colonic lesions compared to other groups. In conclusion, our data indicate that SR-A/CD36 double deficiency leads to more severe colonic lesions and dysregulated inflammatory response as compared with single SR-A or CD36 deficiency in colitis, suggesting additive effects between these two receptors in this model.


Assuntos
Antígenos CD36/metabolismo , Colite/imunologia , Colo/imunologia , Receptores Depuradores Classe A/metabolismo , Anemia/induzido quimicamente , Anemia/genética , Anemia/imunologia , Animais , Peso Corporal , Antígenos CD36/deficiência , Antígenos CD36/genética , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/genética , Proteína Amiloide A Sérica/metabolismo , Índice de Gravidade de Doença , Esplenomegalia/induzido quimicamente , Esplenomegalia/genética , Esplenomegalia/imunologia , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/metabolismo
20.
J Leukoc Biol ; 84(2): 510-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18511575

RESUMO

Apoptotic cells (AC) must be cleared by macrophages (Mø) to resolve inflammation effectively. Mertk and scavenger receptor A (SR-A) are two of many receptors involved in AC clearance. As SR-A lacks enzymatic activity or evident intracellular signaling motifs, yet seems to signal in some cell types, we hypothesized that SR-A signals via Mer receptor tyrosine kinase (Mertk), which contains a multisubstrate docking site. We induced apoptosis in murine thymocytes by dexamethasone and used Western blotting and immunoprecipitation to analyze the interaction of Mertk and SR-A in the J774A.1 (J774) murine Mø cell line and in peritoneal Mø of wild-type mice and SR-A-/- mice. Phagocytosis (but not adhesion) of AC by J774 was inhibited by anti-SR-A or function-blocking SR-A ligands. In resting J774, SR-A was associated minimally with unphosphorylated (monomeric) Mertk; exposure to AC induced a time-dependent increase in association of SR-A with Mertk in a direct or indirect manner. Anti-SR-A inhibited AC-induced phosphorylation of Mertk and of phospholipase Cgamma2, essential steps in AC ingestion. Relative to tissue Mø of wild-type mice, AC-induced Mertk phosphorylation was reduced and delayed in tissue Mø of SR-A-/- mice, as was in vitro AC ingestion at early time-points. Thus, during AC uptake by murine Mø, SR-A is essential for optimal phosphorylation of Mertk and subsequent signaling required for AC ingestion. These data support the Mertk/SR-A complex as a potential target to manipulate AC clearance and hence, resolution of inflammation and infections.


Assuntos
Apoptose/fisiologia , Macrófagos/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Depuradores Classe A/deficiência , Receptores Depuradores Classe A/fisiologia , Animais , Inflamação/fisiopatologia , Camundongos , Camundongos Knockout , Receptores Depuradores Classe A/genética , Linfócitos T/fisiologia , c-Mer Tirosina Quinase
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