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1.
Sci Rep ; 10(1): 159, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932599

RESUMO

Enterovirus-A71 (EV-A71) is a common cause of hand-foot-and-mouth disease (HFMD) and, rarely, causes severe neurological disease. This study aimed to elucidate the epidemiological and genetic characteristics and virulence of EV-A71 strains isolated from children diagnosed with HFMD. Rectal and throat swabs were collected from 488 children with HFMD in Hanoi, Vietnam, in 2015-2016. From 391 EV-positive patients, 15 EVs, including coxsackievirus A6 (CV-A6; 47.1%) and EV-A71 (32.5%, n = 127), were identified. Of the 127 EV-A71 strains, 117 (92.1%) were the B5 subgenotype and 10 (7.9%) were the C4 subgenotype. A whole-genome analysis of EV-A71 strains showed that seven of the eight C4a strains isolated in 2016 formed a new lineage, including two possible recombinants between EV-A71 C4 and CV-A8. The proportion of inpatients among C4-infected children was higher than among B5-infected children (80.0% vs. 27.4%; P = 0.002). The virulence of EV-A71 strains was examined in human scavenger receptor class B2 (hSCARB2)-transgenic mice, and EV-A71 C4 strains exhibited higher mortality than B5 strains (80.0% vs. 30.0%, P = 0.0001). Thus, a new EV-A71 C4a-lineage, including two possible recombinants between EV-A71 C4 and CV-A8, appeared in 2016 in Vietnam. The EV-A71 C4 subgenotype may be more virulent than the B5 subgenotype.


Assuntos
Enterovirus/classificação , Enterovirus/isolamento & purificação , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/mortalidade , Glicoproteínas de Membrana Associadas ao Lisossomo/fisiologia , Receptores Depuradores/fisiologia , Replicação Viral , Animais , Criança , Pré-Escolar , Surtos de Doenças , Enterovirus/genética , Feminino , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Filogenia , Sorogrupo , Taxa de Sobrevida , Fatores de Tempo , Vietnã/epidemiologia
2.
Front Immunol ; 10: 458, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936871

RESUMO

Non-typeable Haemophilus influenzae (NTHi) causes persistent respiratory infections in patients with chronic obstructive pulmonary disease (COPD), probably linked to its capacity to invade and reside within pneumocytes. In the alveolar fluid, NTHi is in contact with pulmonary surfactant, a lipoprotein complex that protects the lung against alveolar collapse and constitutes the front line of defense against inhaled pathogens and toxins. Decreased levels of surfactant phospholipids have been reported in smokers and patients with COPD. The objective of this study was to investigate the effect of surfactant phospholipids on the host-pathogen interaction between NTHi and pneumocytes. For this purpose, we used two types of surfactant lipid vesicles present in the alveolar fluid: (i) multilamellar vesicles (MLVs, > 1 µm diameter), which constitute the tensioactive material of surfactant, and (ii) small unilamellar vesicles (SUVs, 0.1 µm diameter), which are generated after inspiration/expiration cycles, and are endocytosed by pneumocytes for their degradation and/or recycling. Results indicated that extracellular pulmonary surfactant binds to NTHi, preventing NTHi self-aggregation and inhibiting adhesion of NTHi to pneumocytes and, consequently, inhibiting NTHi invasion. In contrast, endocytosed surfactant lipids, mainly via the scavenger receptor SR-BI, did not affect NTHi adhesion but inhibited NTHi invasion by blocking bacterial uptake in pneumocytes. This blockade was made possible by inhibiting Akt phosphorylation and Rac1 GTPase activation, which are signaling pathways involved in NTHi internalization. Administration of the hydrophobic fraction of lung surfactant in vivo accelerated bacterial clearance in a mouse model of NTHi pulmonary infection, supporting the notion that the lipid component of lung surfactant protects against NTHi infection. These results suggest that alterations in surfactant lipid levels in COPD patients may increase susceptibility to infection by this pathogen.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Infecções por Haemophilus/prevenção & controle , Haemophilus influenzae/efeitos dos fármacos , Surfactantes Pulmonares/farmacologia , Células Epiteliais Alveolares/metabolismo , Animais , Aderência Bacteriana/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Vesículas Extracelulares/fisiologia , Infecções por Haemophilus/imunologia , Haemophilus influenzae/isolamento & purificação , Haemophilus influenzae/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos , Masculino , Camundongos , Neuropeptídeos/antagonistas & inibidores , Otite Média/microbiologia , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença Pulmonar Obstrutiva Crônica/microbiologia , Surfactantes Pulmonares/imunologia , Ratos , Ratos Sprague-Dawley , Receptores Depuradores/antagonistas & inibidores , Receptores Depuradores/fisiologia , Organismos Livres de Patógenos Específicos , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
3.
J Virol ; 93(11)2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30894476

RESUMO

Enterovirus 71 (EV71) infection is generally associated with hand-foot-and-mouth disease (HFMD) and may cause severe neurological disorders and even death. An effective murine oral infection model for studying the pathogenesis of various clinical EV71 isolates is lacking. We developed a transgenic (Tg) mouse that expresses an EV71 receptor, that is, human scavenger receptor class B member 2 (hSCARB2), in a pattern highly similar to that of endogenous murine SCARB2 (mSCARB2) protein. A FLAG-tagged SCARB2 cDNA fragment composed of exons 3 to 12 was inserted into a murine Scarb2 gene-containing bacterial artificial chromosome (BAC) clone, and the resulting transgene was used for establishment of chimeric receptor-expressing Tg mice. Tg mice intragastrically (i.g.) infected with clinical isolates of EV71 showed neurological symptoms, such as ataxia and paralysis, and fatality. There was an age-dependent decrease in susceptibility to viral infection. Pathological characteristics of the infected Tg mice resembled those of encephalomyelitis in human patients. Viral infection was accompanied by microglial activation. Clodronate treatment of the brain slices from Tg mice enhanced viral replication, while lipopolysaccharide treatment significantly inhibited it, suggesting an antiviral role for microglia during EV71 infection. Taken together, this Tg mouse provides a model that closely mimics natural infection for studying EV71 pathogenesis and for evaluating the efficacy of vaccines or other antiviral drugs.IMPORTANCE The availability of a murine model of EV71 infection is beneficial for the understanding of pathogenic mechanisms and the development and assessment of vaccines and antiviral drugs. However, the lack of a murine oral infection model thwarted the study of pathogenesis induced by clinically relevant EV71 strains that are transmitted via the oral-oral or oral-fecal route. Our Tg mice could be intragastrically infected with clinically relevant EV71 strains in an efficient way and developed neurological symptoms and pathological changes strikingly resembling those of human infection. Moreover, these mice showed an age-dependent change in susceptibility that is similar to the human case. This Tg mouse, when combined with the use of other genetically modified mice, potentially contributes to studying the relationship between developmental changes in immunity and susceptibility to virus.


Assuntos
Antígenos CD36/metabolismo , Infecções por Enterovirus/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Receptores Depuradores/metabolismo , Animais , Antígenos CD36/fisiologia , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Enterovirus/genética , Enterovirus/metabolismo , Enterovirus Humano A/genética , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/fisiologia , Camundongos , Camundongos Transgênicos , Receptores Depuradores/genética , Receptores Depuradores/fisiologia , Receptores Virais/metabolismo , Replicação Viral
4.
Br J Haematol ; 183(2): 185-195, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30378120

RESUMO

The mechanisms involved in regulating von Willebrand factor (VWF) clearance remain poorly understood. However recent studies have shown that macrophages play a critical role in regulating the half-life of VWF, and have identified specific lectin (including asialoglycoprotein, macrophage galactose-type lectin, Sigec-5 and C-type lectin domain family 4 member M) and scavenger receptors (including low-density lipoprotein receptor-related protein-1, scavenger receptor A1 and stabilin-2) that are involved in VWF clearance. Further studies will be required to determine the relative importance of these individual receptors with respect to physiological and pathological VWF clearance. Nevertheless, recent clinical data have highlighted the importance of enhanced VWF clearance in the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, increased clearance also contributes to reduced VWF levels in many patients with type 2 and type 3 VWD. Improved understanding regarding VWF clearance is not only of direct biological relevance, but may also have important implications for the development of novel therapeutic agents with extended plasma half-lives for the treatment of both VWD and haemophilia A.


Assuntos
Doenças de von Willebrand/sangue , Fator de von Willebrand/metabolismo , Desamino Arginina Vasopressina/uso terapêutico , Hemostáticos/uso terapêutico , Humanos , Mutação , Receptores Mitogênicos/fisiologia , Receptores Depuradores/fisiologia , Relação Estrutura-Atividade , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/etiologia , Fator de von Willebrand/genética
5.
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
6.
Am J Chin Med ; 46(1): 87-106, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29298513

RESUMO

oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.


Assuntos
Andrographis/química , Colesterol/metabolismo , Diterpenos/farmacologia , Células Espumosas/metabolismo , Lipoproteínas LDL/efeitos adversos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anti-Inflamatórios , Antineoplásicos Fitogênicos , Antioxidantes , Aterosclerose/etiologia , Transporte Biológico/genética , Antígenos CD36/genética , Antígenos CD36/metabolismo , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/fisiologia , Camundongos , RNA Mensageiro/metabolismo , Receptores Depuradores/fisiologia
7.
Uirusu ; 68(1): 71-78, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-31105137

RESUMO

Since RNA virus genome encodes only a limited number of viral proteins, replication of RNA virus mostly relies on host cells. Elucidation of host proteins that play important roles in the virus replication cycles contributes not only to fundamental virology research but also to applied research such as development of antiviral drugs. We revealed that Ebola virus matrix protein VP40 utilized host COPII transport machinery for its intracellular transport to the plasma membrane. Second, we demonstrated that enterovirus A71 used Scavenger receptor class B member 2 (SCARB2) as a cellular receptor. Finally, we found that host protein CLUH played an important role in the subnuclear transport of influenza virus ribonucleoprotein (vRNP) complexes. Here, I would like to briefly introduce these findings.


Assuntos
Vesículas Revestidas pelo Complexo de Proteína do Envoltório/fisiologia , Interações Hospedeiro-Patógeno/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/fisiologia , Vírus de RNA/fisiologia , Proteínas de Ligação a RNA/fisiologia , Receptores Depuradores/fisiologia , Replicação Viral/genética , Transporte Ativo do Núcleo Celular , Animais , Humanos , Camundongos , Vírus de RNA/genética , Proteínas da Matriz Viral/metabolismo
8.
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
9.
Lipids Health Dis ; 16(1): 30, 2017 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28166809

RESUMO

Atherosclerosis is considered as an inflammatory and chronic disorder with an important immunologic component, which underlies the majority of cardiovascular diseases; condition that belongs to a group of noncommunicable diseases that to date and despite of prevention and treatment approaches, they remain as the main cause of death worldwide, with 17.5 million of deaths every year. The impact of lipids in human health and disease is taking center stage in research, due to lipotoxicity explained by elevated concentration of circulating lipids, in addition to altered adipose tissue metabolism, and aberrant intracellular signaling. Immune response and metabolic regulation are highly integrated systems and the proper function of each one is dependent on the other. B lymphocytes express a variety of receptors that can recognize foreign, endogenous or modified self-antigens, among them oxidized low density lipoproteins, which are the main antigens in atherosclerosis. Mechanisms of B cells to recognize, remove and present lipids are not completely clear. However, it has been reported that B cell can recognize/remove lipids through a range of receptors, such as LDLR, CD1d, FcR and SR, which might have an atheroprotector or proatherogenic role during the course of atherosclerotic disease. Pertinent literature related to these receptors was examined to inform the present conclusions.


Assuntos
Aterosclerose/imunologia , Linfócitos B/imunologia , Animais , Humanos , Imunidade Celular , Lipoproteínas LDL/imunologia , Receptores Depuradores/fisiologia
10.
Biochim Biophys Acta ; 1860(6): 1118-28, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26922829

RESUMO

BACKGROUND: C-reactive protein (CRP) is a plasma pentraxin family protein that is massively induced as part of the innate immune response to infection and tissue injury. CRP and other pentraxin proteins can activate a complement pathway through C1q, collectins, or on microbe surfaces. It has been found that a lectin-like oxidized LDL receptor 1 (LOX-1), which is an endothelial scavenger receptor (SR) having a C-type lectin-like domain, interacts with CRP to activate the complement pathway using C1q. However it remains elusive whether other lectins or SRs are involved in CRP-mediated complement activation and the downstream effect of the complement activation is also unknown. METHODS: We prepared CHO/ldlA7 cells expressing collectin placenta-1 (CL-P1) and studied the interaction of CRP with cells. We further used ELISA for testing binding between proteins. We tested for C3 fragment deposition and terminal complement complex (TCC) formation on HEK293 cells expressing CL-P1. RESULTS: Here, we demonstrated that CL-P1 bound CRP in a charge dependent manner and the interaction of CRP with CL-P1 mediated a classical complement activation pathway through C1q and additionally drove an amplification pathway using properdin. However, CRP also recruits complement factor H (CFH) on CL-P1 expressing cell surfaces, to inhibit the formation of a terminal complement complex in normal complement serum conditions. GENERAL SIGNIFICANCE: The interaction of collectin CL-P1 with CFH might be key for preventing attack on "self" as a result of complement activation induced by the CL-P1 and CRP interaction.


Assuntos
Proteína C-Reativa/química , Colectinas/química , Ativação do Complemento , Receptores Depuradores/química , Animais , Proteína C-Reativa/fisiologia , Células CHO , Colectinas/fisiologia , Fator H do Complemento/química , Cricetulus , Células HEK293 , Humanos , Receptores Depuradores/fisiologia
11.
Cardiovasc Res ; 109(1): 24-33, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26472132

RESUMO

Scavenger receptors (SRs), which recognize modified low-density lipoprotein (LDL) by oxidation or acetylation, are a group of receptors on plasma membrane of macrophages and other cell types. These receptors by facilitating modified LDL uptake are a primary step in the intracellular accumulation of modified LDL and formation of fatty streak. Non-coding RNAs (ncRNAs) are a group of functional RNA nucleotides that are not translated into protein, and include microRNAs (miRs), snoRNAs, siRNAs, snRNAs, exRNAs, piRNAs, and the long ncRNAs (lncRNAs). Recently, ncRNAs have received much attention due to their effects in a variety of disease states such as atherosclerotic cardiovascular disease and cancers. A host of ncRNAs, such as miRs and lncRNAs, have been found to be involved in the regulation of SRs and the inflammatory cascade and subsequently atherosclerosis. Here, we review this important area to create interest in this growing field among researchers and clinicians alike.


Assuntos
Aterosclerose/etiologia , RNA não Traduzido/fisiologia , Receptores Depuradores/fisiologia , Animais , Humanos , Receptores Depuradores/classificação
12.
Cancer Sci ; 107(3): 290-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26708384

RESUMO

Wnt5a-Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell-autonomous manner. However, little is known about its function in cancer-associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a-Ror2 signaling in bone marrow-derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Coculture of a gastric cancer cell line, MKN45, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to coculture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a-Ror2 signaling, and that recombinant chemokine (C-X-C motif) ligand (CXCL)16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect coculture with MSCs. Importantly, we show that MKN45 cells express chemokine (C-X-C motif) receptor (CXCR)6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect coculture with MSCs. These findings indicate that Wnt5a-Ror2 signaling enhances expression of CXCL16 in MSCs and, as a result, enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation.


Assuntos
Quimiocinas CXC/fisiologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores Depuradores/fisiologia , Receptores Virais/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Wnt/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL16 , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores CXCR6 , Transdução de Sinais , Neoplasias Gástricas/patologia , Ativação Transcricional , Proteína Wnt-5a
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 32(5): 723-7, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26419000

RESUMO

SCARB2 (scavenger receptor class B, member 2) is a lysosomal membrane glucoprotein, which is encoded by SCARB2 gene. It takes vital parts in the physiological and pathological processes including the transportation of beta-glucocerebrosidase to the lysosome, infection of EV71 and load-induced cardiac myocyte hypertrophy. This article has reviewed the molecular structure and functions of SCARB2 gene and its protein, as well as their relationship with diseases.


Assuntos
Glicoproteínas de Membrana Associadas ao Lisossomo/fisiologia , Receptores Depuradores/fisiologia , Doença de Mão, Pé e Boca/genética , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/química , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Epilepsias Mioclônicas Progressivas/genética , Doença de Parkinson/genética , Receptores Depuradores/química , Receptores Depuradores/genética
14.
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
15.
Redox Biol ; 2: 411-29, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24624331

RESUMO

Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.


Assuntos
Produtos Finais de Glicação Avançada/fisiologia , Inflamação/etiologia , Receptores Imunológicos/fisiologia , Transdução de Sinais/fisiologia , Envelhecimento/fisiologia , Animais , Osso e Ossos/metabolismo , Proteínas na Dieta/efeitos adversos , Proteínas na Dieta/farmacocinética , Humanos , Hiperglicemia/metabolismo , Sistema Imunitário/metabolismo , Inflamação/metabolismo , Peroxidação de Lipídeos , Pulmão/metabolismo , Reação de Maillard , Modelos Biológicos , NF-kappa B/fisiologia , Neurônios/metabolismo , Estresse Oxidativo/fisiologia , Polímeros/metabolismo , Agregados Proteicos , Transporte Proteico , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Depuradores/fisiologia
16.
J Leukoc Biol ; 94(5): 885-902, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23990624

RESUMO

TLRs play a major role in microbe-host interactions and innate immunity. Of the 10 functional TLRs described in humans, TLR2 is unique in its requirement to form heterodimers with TLR1 or TLR6 for the initiation of signaling and cellular activation. The ligand specificity of TLR2 heterodimers has been studied extensively, using specific bacterial and synthetic lipoproteins to gain insight into the structure-function relationship, the minimal active motifs, and the critical dependence on TLR1 or TLR6 for activation. Different from that for specific well-defined TLR2 agonists, recognition of more complex ligands like intact microbes or molecules from endogenous origin requires TLR2 to interact with additional coreceptors. A breadth of data has been published on ligand-induced interactions of TLR2 with additional pattern recognition receptors such as CD14, scavenger receptors, integrins, and a range of other receptors, all of them important factors in TLR2 function. This review summarizes the roles of TLR2 in vivo and in specific immune cell types and integrates this information with a detailed review of our current understanding of the roles of specific coreceptors and ligands in regulating TLR2 functions. Understanding how these processes affect intracellular signaling and drive functional immune responses will lead to a better understanding of host-microbe interactions and will aid in the design of new agents to target TLR2 function in health and disease.


Assuntos
Receptores Imunológicos/fisiologia , Receptor 2 Toll-Like/fisiologia , Animais , Humanos , Mediadores da Inflamação/fisiologia , Integrinas/fisiologia , Lectinas/fisiologia , Receptores de Lipopolissacarídeos/fisiologia , Lipopolissacarídeos/fisiologia , Microdomínios da Membrana/fisiologia , Polimorfismo de Nucleotídeo Único , Multimerização Proteica , Receptores CXCR4/fisiologia , Receptores de Reconhecimento de Padrão/fisiologia , Receptores Depuradores/fisiologia , Ácidos Teicoicos , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/química
17.
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
18.
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 , Proteínas de Ligação ao Cálcio , Doença Crônica , Proteínas de Ligação a DNA , 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 , Proteínas Supressoras de Tumor
19.
Arthritis Rheum ; 65(7): 1736-46, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23633118

RESUMO

OBJECTIVE: To examine the possibility that CXCL16 recruits endothelial cells (ECs) to developing neovasculature in rheumatoid arthritis (RA) synovium. METHODS: We utilized the RA synovial tissue SCID mouse chimera system to examine human microvascular EC (HMVEC) and human endothelial progenitor cell (EPC) recruitment into engrafted human synovium that was injected intragraft with CXCL16-immunodepleted RA synovial fluid (SF). CXCR6-deficient and wild-type (WT) C57BL/6 mice were primed to develop K/BxN serum-induced arthritis and evaluated for angiogenesis. HMVECs and EPCs from human cord blood were also examined for CXCR6 expression, by immunofluorescence and assessment of CXCL16 signaling activity. RESULTS: CXCR6 was prominently expressed on human EPCs and HMVECs, and its expression on HMVECs could be up-regulated by interleukin-1ß. SCID mice injected with CXCL16-depleted RA SF exhibited a significant reduction in EPC recruitment. In experiments using the K/BxN serum-induced inflammatory arthritis model, CXCR6(-/-) mice showed profound reductions in hemoglobin levels, which correlated with reductions in monocyte and T cell recruitment to arthritic joint tissue compared to that observed in WT mice. Additionally, HMVECs and EPCs responded to CXCL16 stimulation, but exhibited unique signal transduction pathways and homing properties. CONCLUSION: These results indicate that CXCL16 and its receptor CXCR6 may be a central ligand/receptor pair that is closely associated with EPC recruitment and blood vessel formation in the RA joint.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Quimiocina CXCL6/fisiologia , Quimiocinas CXC/fisiologia , Células Endoteliais/fisiologia , Neovascularização Patológica/metabolismo , Receptores CXCR/fisiologia , Receptores de Quimiocinas/fisiologia , Receptores Depuradores/fisiologia , Receptores Virais/fisiologia , Animais , Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Quimiocina CXCL16 , Quimiotaxia/fisiologia , Células Endoteliais/metabolismo , Humanos , Interleucina-1beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , Neovascularização Patológica/fisiopatologia , Receptores CXCR/efeitos dos fármacos , Receptores CXCR/genética , Receptores CXCR6 , Receptores de Quimiocinas/metabolismo , Receptores Virais/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Membrana Sinovial/metabolismo
20.
Am J Physiol Regul Integr Comp Physiol ; 303(12): R1217-30, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23076875

RESUMO

To maintain homeostasis, the animal body is equipped with a powerful system to remove circulating waste. This review presents evidence that the scavenger endothelial cell (SEC) is responsible for the clearance of blood-borne waste macromolecules in vertebrates. SECs express pattern-recognition endocytosis receptors (mannose and scavenger receptors), and in mammals, the endocytic Fc gamma-receptor IIb2. This cell type has an endocytic machinery capable of super-efficient uptake and degradation of physiological and foreign waste material, including all major classes of biological macromolecules. In terrestrial vertebrates, most SECs line the wall of the liver sinusoid. In phylogenetically older vertebrates, SECs reside instead in heart, kidney, or gills. SECs, thus, by virtue of their efficient nonphagocytic elimination of physiological and microbial substances, play a critical role in the innate immunity of vertebrates. In major invertebrate phyla, including insects, the same function is carried out by nephrocytes. The concept of a dual-cell principle of waste clearance is introduced to emphasize that professional phagocytes (macrophages in vertebrates; hemocytes in invertebrates) eliminate larger particles (>0.5 µm) by phagocytosis, whereas soluble macromolecules and smaller particles are eliminated efficiently and preferentially by clathrin-mediated endocytosis in nonphagocytic SECs in vertebrates or nephrocytes in invertebrates. Including these cells as important players in immunology and physiology provides an additional basis for understanding host defense and tissue homeostasis.


Assuntos
Células Endoteliais/fisiologia , Homeostase/fisiologia , Imunidade/fisiologia , Receptores Depuradores/fisiologia , Envelhecimento/fisiologia , Animais , Endocitose/fisiologia , Humanos , Néfrons/fisiologia
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