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1.
Autoimmunity ; 57(1): 2201412, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38425093

RESUMO

OBJECTIVE: To explore the effect of CD5-like molecule (CD5L) on rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) and the relative molecular mechanism of CD5L in it. METHODS: Recombinant protein CD5L was used to stimulate the cultured RA-FLS cells. The inflammation-related cytokines were determined by real time-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The signal molecules and apoptosis-related molecules were detected by western blot assay (WB), and cell counting kit-8 (CCK-8) was used to detect the proliferation. RESULTS: CD5L can increase the production of IL-6, IL-8, and TNF-α and this effect can be inhibited by signal pathway inhibitor. At the same time, CD5L activated ERK1/2 MAPK signal, inhibitor treatment can weaken the intensity of phosphorylation. In addition, CD5L can enhance the proliferation ability of RA-FLS. CONCLUSION: CD5L induces the production of inflammatory cytokines in RA-FLS through the ERK1/2 MAPK pathway and increases cell survival.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Humanos , Membrana Sinovial/metabolismo , Sistema de Sinalização das MAP Quinases , Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Proliferação de Células , Proteínas Reguladoras de Apoptose , Receptores Depuradores/metabolismo
2.
Methods Mol Biol ; 2789: 293-298, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38507011

RESUMO

Nanoparticles can be cleared from the circulation and taken up by tissue-resident macrophages. This property can be beneficial when drug or antigen delivery to macrophages is desired; however, rapid clearance of nanoparticles not intended for delivery to immune cells may reduce nanoparticle circulation time and affect the efficacy of nanoparticle-formulated drug products. Therefore, understanding nanoparticles' uptake by macrophages is an essential step in the preclinical development of nanotechnology-based drug products. Understanding the route of nanoparticle uptake by macrophages may also provide mechanistic insights into the immunotoxicity of nanomaterials. The protocol described herein can be used to assess the nanoparticles' uptake by macrophages and understand the involvement of scavenger receptor A1 to inform mechanistic studies.


Assuntos
Macrófagos , Nanopartículas , Animais , Camundongos , Receptores Depuradores , Nanotecnologia , Nanopartículas/toxicidade , Receptores Depuradores Classe A
3.
PLoS Pathog ; 20(2): e1012022, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38359079

RESUMO

Enterovirus A71 (EV-A71) infection involves a variety of receptors. Among them, two transmembrane protein receptors have been investigated in detail and shown to be critical for infection: P-selectin glycoprotein ligand-1 (PSGL-1) in lymphocytes (Jurkat cells), and scavenger receptor class B member 2 (SCARB2) in rhabdomyosarcoma (RD) cells. PSGL-1 and SCARB2 have been reported to be expressed on the surface of Jurkat and RD cells, respectively. In the work reported here, we investigated the roles of PSGL-1 and SCARB2 in the process of EV-A71 entry. We first examined the expression of SCARB2 in Jurkat cells, and detected it within the cytoplasm, but not on the cell surface. Further, using PSGL-1 and SCARB2 knockout cells, we found that although both PSGL-1 and SCARB2 are essential for virus infection of Jurkat cells, virus attachment to these cells requires only PSGL-1. These results led us to evaluate the cell surface expression and the roles of SCARB2 in other EV-A71-susceptible cell lines. Surprisingly, in contrast to the results of previous studies, we found that SCARB2 is absent from the surface of RD cells and other susceptible cell lines we examined, and that although SCARB2 is essential for infection of these cells, it is dispensable for virus attachment. These results indicate that a receptor other than SCARB2 is responsible for virus attachment to the cell and probably for internalization of virions, not only in Jurkat cells but also in RD cells and other EV-A71-susceptible cells. SCARB2 is highly concentrated in lysosomes and late endosomes, where it is likely to trigger acid-dependent uncoating of virions, the critical final step of the entry process. Our results suggest that the essential interactions between EV-A71 and SCARB2 occur, not at the cell surface, but within the cell.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Humanos , Enterovirus/metabolismo , Enterovirus Humano A/genética , Enterovirus Humano A/metabolismo , Membrana Celular/metabolismo , Linhagem Celular , Receptores Depuradores/genética , Receptores Depuradores/metabolismo , /genética
4.
Fish Shellfish Immunol ; 147: 109433, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38336143

RESUMO

SRC gene encodes scavenger receptor class C, a member of the scavenger receptor family, and has only been identified and investigated in invertebrates. Our previous studies have revealed that SRC is a novel candidate gene associated with body weight in Pacific white shrimp (Litopenaeus vannamei). In order to comprehend the underlying mechanism by which LvSRC affects shrimp growth, we analyzed the structure, phylogeny, expression profiles and RNA interference (RNAi) of this gene in L. vannamei. We found that LvSRC contains two CCP domains and one MAM domain, with the highest expression level in the heart and relatively low expression level in other tissues. Notably, LvSRC exhibited significantly higher expression levels in the fast-growing group among groups with different growth rates, suggesting its potential involvement as a gene contributing to the growth of L. vannamei. RNAi of LvSRC inhibited body length and body weight gain compared to the control groups. Moreover, through RNA-seq analysis, we identified 598 differentially expressed genes (DEGs), including genes associated with growth, immunity, protein processing and modification, signal transduction, lipid synthesis and metabolism. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant changes in the signaling pathways related to growth, lipid metabolism and immune response, suggesting that LvSRC exhibits the potential to participate in diverse physiological processes and immune regulation. These findings deepen our understanding of the structure and function of the SRC in shrimp and lay the foundation for further research into the regulatory mechanism of LvSRC. Additionally, they provide potential applications in shrimp genetics and breeding.


Assuntos
Genes src , Penaeidae , Animais , Transdução de Sinais , Perfilação da Expressão Gênica , Peso Corporal , Receptores Depuradores/genética
5.
Nat Commun ; 15(1): 1663, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38396109

RESUMO

Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecular co-assembly system consisting of two self-assembling peptide ligands that bind cell membrane receptors and the protein of interest simultaneously, resulting in targeted protein degradation. The developed lysosome-targeting co-assemblies (LYTACAs) can induce lysosomal degradation of extracellular protein IL-17A and membrane protein PD-L1 in several scavenger receptor A-expressing cell lines. The IL-17A-degrading co-assembly has been applied in an imiquimod-induced psoriasis mouse model, where it decreases IL-17A levels in the skin lesion and alleviates psoriasis-like inflammation. Extending to asialoglycoprotein receptor-related protein degradation, LYTACAs have demonstrated the versatility and potential in streamlining degraders for extracellular and membrane proteins.


Assuntos
Psoríase , Pele , Animais , Camundongos , Pele/patologia , Interleucina-17/metabolismo , Proteólise , Psoríase/metabolismo , Receptores Depuradores/metabolismo , Proteínas de Membrana/metabolismo , Lisossomos/metabolismo , Modelos Animais de Doenças
6.
Int J Mol Sci ; 25(3)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38338794

RESUMO

Without general adaptative immunity, invertebrates evolved a vast number of heterogeneous non-self recognition strategies. One of those well-known adaptations is the expansion of the immune receptor gene superfamily coding for scavenger receptor cysteine-rich domain containing proteins (SRCR) in a few invertebrates. Here, we investigated the evolutionary history of the SRCR gene superfamily (SRCR-SF) across 29 metazoan species with an emphasis on invertebrates. We analyzed their domain architectures, genome locations and phylogenetic distribution. Our analysis shows extensive genome-wide duplications of the SRCR-SFs in Amphimedon queenslandica and Strongylocentrotus purpuratus. Further molecular evolution study reveals various patterns of conserved cysteines in the sponge and sea urchin SRCR-SFs, indicating independent and convergent evolution of SRCR-SF expansion during invertebrate evolution. In the case of the sponge SRCR-SFs, a novel motif with seven conserved cysteines was identified. Exon-intron structure analysis suggests the rapid evolution of SRCR-SFs during gene duplications in both the sponge and the sea urchin. Our findings across nine representative metazoans also underscore a heightened expression of SRCR-SFs in immune-related tissues, notably the digestive glands. This observation indicates the potential role of SRCR-SFs in reinforcing distinct immune functions in these invertebrates. Collectively, our results reveal that gene duplication, motif structure variation, and exon-intron divergence might lead to the convergent evolution of SRCR-SF expansions in the genomes of the sponge and sea urchin. Our study also suggests that the utilization of SRCR-SF receptor duplication may be a general and basal strategy to increase immune diversity and tissue specificity for the invertebrates.


Assuntos
Invertebrados , Receptores Imunológicos , Animais , Receptores Depuradores/genética , Filogenia , Receptores Imunológicos/genética , Invertebrados/genética , Ouriços-do-Mar/genética , Evolução Molecular
7.
Cell Commun Signal ; 22(1): 97, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308264

RESUMO

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.


Assuntos
Lesão Pulmonar Aguda , Armadilhas Extracelulares , Sepse , Humanos , Camundongos , Animais , Armadilhas Extracelulares/metabolismo , Síndrome da Liberação de Citocina , Espécies Reativas de Oxigênio/metabolismo , Neutrófilos/metabolismo , Inflamação/metabolismo , Sepse/complicações , Sepse/metabolismo , Lesão Pulmonar Aguda/metabolismo , Receptores Depuradores/metabolismo
8.
Int J Biol Macromol ; 260(Pt 2): 129387, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38253150

RESUMO

Carotenoid based body coloration are common features in fish, which depends on the diet derived carotenoids pigments deposition, employing a bunch of carotenoid uptake, absorption and processing related genes. Scavenger receptors are a large family of cell surface receptors with complex structure and diverse functions. However, the SRs genes have been insufficiently explored concerning their role in fish carotenoid coloration. Here, we systemically identified 19 SRs family genes and investigated their expression patterns of in various tissues of P. leopardus. Expression analysis unveiled the diverse involvements of SRs in the intestine of P. leopardus with different body colors and the responses to exogenous carotenoids. Notably, cd36, emerged as a pivotal factor in intestinal functions predominantly localized in the intestinal epithelial and goblet cells. Knockdown of cd36 led to the reduction in skin brightness and carotenoid levels in both intestine and skin, while overexpressing cd36 increased the carotenoids uptake of cells in vitro. Additionally, our investigations revealed that cd36 exerts regulation on genes associated with carotenoid uptake, transport, and processing. To sum up, our results provide a comprehensive view on SRs functions in carotenoid coloration of P. leopardus and will facilitate the understanding on the mechanism of carotenoids coloration of vertebrates.


Assuntos
Bass , Animais , Carotenoides/análise , Intestinos/química , Receptores Depuradores , Pigmentação
9.
Nat Commun ; 15(1): 621, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245530

RESUMO

Intratumoral immune status influences tumor therapeutic response, but it remains largely unclear how the status determines therapies for patients with intrahepatic cholangiocarcinoma. Here, we examine the single-cell transcriptional and TCR profiles of 18 tumor tissues pre- and post- therapy of gemcitabine plus oxaliplatin, in combination with lenvatinib and anti-PD1 antibody for intrahepatic cholangiocarcinoma. We find that high CD8 GZMB+ and CD8 proliferating proportions and a low Macro CD5L+ proportion predict good response to the therapy. In patients with a poor response, the CD8 GZMB+ and CD8 proliferating proportions are increased, but the CD8 GZMK+ proportion is decreased after the therapy. Transition of CD8 proliferating and CD8 GZMB+ to CD8 GZMK+ facilitates good response to the therapy, while Macro CD5L+-CD8 GZMB+ crosstalk impairs the response by increasing CTLA4 in CD8 GZMB+. Anti-CTLA4 antibody reverses resistance of the therapy in intrahepatic cholangiocarcinoma. Our data provide a resource for predicting response of the combination therapy and highlight the importance of CD8+T-cell status conversion and exhaustion induced by Macro CD5L+ in influencing the response, suggesting future avenues for cancer treatment optimization.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Compostos de Fenilureia , Quinolinas , Humanos , Oxaliplatina/uso terapêutico , Gencitabina , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Linfócitos T CD8-Positivos , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Proteínas Reguladoras de Apoptose , Receptores Depuradores
10.
Cell Mol Life Sci ; 81(1): 62, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38280036

RESUMO

Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.


Assuntos
Aterosclerose , Células Endoteliais , Camundongos , Animais , Células Endoteliais/metabolismo , Lipoproteínas LDL/farmacologia , Lipoproteínas LDL/metabolismo , Aterosclerose/metabolismo , NF-kappa B/metabolismo , Receptores Depuradores/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo
11.
Eur Heart J ; 45(4): 268-283, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38036416

RESUMO

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.


Assuntos
Aterosclerose , Células Espumosas , Receptores Purinérgicos P2 , Humanos , Camundongos , Animais , Células Espumosas/metabolismo , Células Espumosas/patologia , Cálcio/metabolismo , Calreticulina/metabolismo , Calreticulina/farmacologia , Proteômica , Tiamina Pirofosfato/metabolismo , Tiamina Pirofosfato/farmacologia , Aterosclerose/genética , Macrófagos/metabolismo , Lipoproteínas LDL/metabolismo , Receptores Depuradores/metabolismo , Camundongos Knockout , Fosfolipases/metabolismo , Fosfolipases/farmacologia
12.
Chem Phys Lipids ; 258: 105362, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38006924

RESUMO

The onset and progression of cardiovascular diseases with the major underlying cause being atherosclerosis, occur during chronic inflammatory persistence in the vascular system, especially within the arterial wall. Such prolonged maladaptive inflammation is driven by macrophages and their key mediators are generally attributed to a disparity in lipid metabolism. Macrophages are the primary cells of innate immunity, endowed with expansive membrane domains involved in immune responses with their signalling systems. During atherosclerosis, the membrane domains and receptors control various active organisations of macrophages. Their scavenger/endocytic receptors regulate the trafficking of intracellular and extracellular cargo. Corresponding influence on lipid metabolism is mediated by their dynamic interaction with scavenger membrane receptors and their integrated mechanisms such as pinocytosis, phagocytosis, cholesterol export/import, etc. This interaction not only results in the functional differentiation of macrophages but also modifies their structural configurations. Here, we reviewed the association of macrophage membrane biomechanics and their scavenger receptor families with lipid metabolites during the event of atherogenesis. In addition, the membrane structure of macrophages and the signalling pathways involved in endocytosis integrated with lipid metabolism are detailed. This article establishes future insights into the scavenger receptors as potential targets for cardiovascular disease prevention and treatment.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/metabolismo , Macrófagos , Receptores Depuradores/metabolismo , Colesterol/metabolismo , Inflamação/metabolismo
13.
J Leukoc Biol ; 115(2): 322-333, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-37726110

RESUMO

Scavenger receptor A (SRA) is preferentially expressed in macrophages and implicated as a multifunctional pattern recognition receptor for innate immunity. Hepatic macrophages play a primary role in the pathogenesis of alcoholic liver disease. Herein, we observed that SRA expression was significantly increased in the liver tissues of mice with alcohol-related liver injury. SRA-deficient (SRA-/-) mice developed more severe alcohol-induced liver disease than wild-type mice. Enhanced liver inflammation existed in alcohol-challenged SRA-/- mice and was associated with increased Notch activation in hepatic macrophages compared with wild-type control animals. Mechanistically, SRA directly bound with Notch1 and suppressed its S-glutathionylation, thereby inhibiting Notch pathway activation. Further, we determined that the SRA interacted with thioredoxin-1 (Trx-1), a redox-active protein. SRA inhibited Trx-1 dimerization and facilitated the interaction of Trx-1 with Notch1. Application of a Trx-1-specific inhibitory agent during macrophage stimulation abolished SRA-mediated regulation of the Notch pathway and its downstream targets. In summary, our study revealed that SRA plays a critical role in macrophage inflammatory response by targeting Notch1 for its glutathionylation. SRA-mediated negative regulation of Notch activation might serve as a novel therapeutic strategy for alcohol-induced liver injury.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Camundongos , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Receptores Depuradores Classe A/metabolismo , Macrófagos/metabolismo , Receptores Depuradores/metabolismo , Fígado/metabolismo , Fatores Imunológicos , Etanol/toxicidade , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Poult Sci ; 103(2): 103318, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38064884

RESUMO

Backyard poultry flocks that employ heritage breeds of chicken play a crucial role in the maintenance of poultry pathogens of economic and zoonotic importance. This study examined innate immunity to viral pathogens in heritage chicken breeds using a model of viral double-stranded RNA (dsRNA). Following intraperitoneal injection of high molecular weight (HMW) -poly(I:C)/Lyovec into 4-wk-old chicks, we evaluated gene expression in peripheral blood mononuclear cells (PBMCs) and splenocytes. There was a significant difference across breeds in the expression of IL-4, IL-12p40, IFNγ, and B-cell activating factor (BAFF) in the spleen. In PBMCs, a significant difference in IFN-α expression was seen across breeds. Approximately 57% of IFN-α transcripts in PBMCs was explained by levels of expression of MDA5 transcripts. Using flow cytometry, we showed that only monocytes/macrophages (KUL01+ cells) expressed the scavenger receptor CD163. Regression analysis showed that 42% of fold change in CD163 expression on PBMCs was explained by breed (P < 0.0004). In general, breeds that responded to HMW-poly(I:C) by showing higher upregulation of IFNγ, IL-1ß, and IL-12p40 transcripts in the spleen, and higher IFNα transcripts in peripheral blood, expressed less CD163 on blood monocytes. These findings suggest a genetic basis for the response of chickens to double-stranded RNA. Surface expression of the scavenger receptor CD163 in PBMCs following injection of high molecular weight poly(I:C) may be a rapid method to select chickens for breeding based on innate immune response to viral dsRNA.


Assuntos
Galinhas , Leucócitos Mononucleares , Animais , Galinhas/genética , RNA de Cadeia Dupla , Subunidade p40 da Interleucina-12 , Imunidade Inata/genética , Poli I-C/farmacologia , Receptores Depuradores
15.
Fish Shellfish Immunol ; 144: 109307, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38122953

RESUMO

Scavenger receptors (SRs) are pattern recognition receptors involved in the innate immune defense against pathogen infection in fish. However, there has not been much research done on teleosts. In this study, 18 members of the SR gene family were found in large yellow croaker. The identification of the SR gene family showed that the protein length of SR members in large yellow croaker were quite different, and most SR genes were distributed in nuclear and endoplasmic. The evolutionary relationship, exon/intron structure and motif analysis revealed that members of the SR gene family were highly conserved. The results of the expression profiles after Pseudomonas plecoglossicida infection and hypoxia-exposure demonstrated that SR members were involved in inflammatory reactions. Especially, COLEC12 and SCARF1 exhibited substantial changes in response to both P. plecoglossicida and hypoxia stress, indicating their possible immunological functions. The result of this study revealed that SR genes played a vital part in the innate immune response of large yellow croaker, and would give important details for a deeper comprehension of the SR gene family's regulation mechanism under various conditions in large yellow croaker.


Assuntos
Doenças dos Peixes , Perciformes , Infecções por Pseudomonas , Animais , Receptores Depuradores , Imunidade Inata/genética , Hipóxia/veterinária , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo
16.
Technol Cancer Res Treat ; 22: 15330338231218163, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38112409

RESUMO

PURPOSE: Collectin subfamily member 12, a transmembrane scavenger receptor C-type lectin, is aberrantly expressed in various cancers. However, its physiological role in gastric cancer remains somewhat unclear. This study aimed to investigate the Collectin subfamily member 12 expression pattern in human gastric cancer and its role in gastric cancer progression. METHODS: The Kaplan-Meier method was used for survival analysis. The univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for progression-free survival and overall survival. The effects of Collectin subfamily member 12 on gastric cancer cell proliferation, migration, invasion, and apoptosis were detected through the cell counting kit-8 assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry analysis, respectively. Additionally, the correlation between Collectin subfamily member 12 expression and immune cell infiltration was analyzed through bioinformatics. RESULTS: Collectin subfamily member 12 was highly expressed in advanced gastric cancer (T3-T4, pathologic stage III-IV). High Collectin subfamily member 12 expression was correlated with a worse progression-free survival and overall survival in the gastric cancer patients. In vitro, cell line studies revealed that Collectin subfamily member 12 promoted gastric cancer cell proliferation, migration, and invasion and inhibited gastric cancer cell apoptosis. The bioinformatics analysis further demonstrated that the Collectin subfamily member 12 expression level positively correlated with infiltration of several immune cells, such as M2 macrophages, dendritic cells, neutrophils, and regulatory T cells, suggesting that Collectin subfamily member 12 may also play a role in suppressing tumor immune response in gastric cancer. CONCLUSIONS: Collectin subfamily member 12 was identified as a novel predictive marker and target for the clinical treatment of gastric cancer.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Prognóstico , Biomarcadores Tumorais/metabolismo , Análise de Sobrevida , Colectinas , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores Depuradores
17.
ACS Infect Dis ; 9(11): 2133-2140, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37910786

RESUMO

The success of Staphylococcus aureus as a major cause for endovascular infections depends on effective interactions with blood-vessel walls. We have previously shown that S. aureus uses its wall teichoic acid (WTA), a surface glycopolymer, to attach to endothelial cells. However, the endothelial WTA receptor remained unknown. We show here that the endothelial oxidized low-density lipoprotein receptor 1 (LOX-1) interacts with S. aureus WTA and permits effective binding of S. aureus to human endothelial cells. Purified LOX-1 bound to isolated S. aureus WTA. Ectopic LOX-1 expression led to increased binding of S. aureus wild type but not of a WTA-deficient mutant to a cell line, and LOX-1 blockage prevented S. aureus binding to endothelial cells. Moreover, WTA and LOX-1 expression levels correlated with the efficacy of the S. aureus-endothelial interaction. Thus, LOX-1 is an endothelial ligand for S. aureus, whose blockage may help to prevent or treat severe endovascular infections.


Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Células Endoteliais , Ácidos Teicoicos/metabolismo , Receptores Depuradores/metabolismo , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/metabolismo
18.
Am J Chin Med ; 51(8): 2175-2193, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37930331

RESUMO

Andrographolide (AND) is a bioactive component of the herb Andrographis paniculata and a well-known anti-inflammatory agent. Atherosclerosis is a chronic inflammatory disease of the vasculature, and oxidized LDL (oxLDL) is thought to contribute heavily to atherosclerosis-associated inflammation. The aim of this study was to investigate whether AND mitigates oxLDL-mediated foam cell formation and diet-induced atherosclerosis (in mice fed a high-fat, high-cholesterol, high-cholic acid [HFCCD] diet) and the underlying mechanisms involved. AND attenuated LPS/oxLDL-mediated foam cell formation, IL-1[Formula: see text] mRNA and protein (p37) expression, NLR family pyrin domain containing 3 (NLRP3) mRNA and protein expression, caspase-1 (p20) protein expression, and IL-1[Formula: see text] release in BMDMs. Treatment with oxLDL significantly induced protein and mRNA expression of CD36, lectin-like oxLDL receptor-1 (LOX-1), and scavenger receptor type A (SR-A), whereas pretreatment with AND significantly inhibited protein and mRNA expression of SR-A only. Treatment with oxLDL significantly induced ROS generation and Dil-oxLDL uptake; however, pretreatment with AND alleviated oxLDL-induced ROS generation and Dil-oxLDL uptake. HFCCD feeding significantly increased aortic lipid accumulation, ICAM-1 expression, and IL-1[Formula: see text] mRNA expression, as well as blood levels of glutamic pyruvic transaminase (GPT), total cholesterol, and LDL-C. AND co-administration mitigated aortic lipid accumulation, the protein expression of ICAM-1, mRNA expression of IL-1[Formula: see text] and ICAM-1, and blood levels of GPT. These results suggest that the working mechanisms by which AND mitigates atherosclerosis involve the inhibition of foam cell formation and NLRP3 inflammasome-dependent vascular inflammation as evidenced by decreased SR-A expression and IL-1[Formula: see text] release, respectively.


Assuntos
Aterosclerose , Inflamassomos , Animais , Camundongos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Macrófagos/metabolismo , Lipoproteínas LDL , Células Espumosas/metabolismo , Receptores Depuradores , Inflamação/metabolismo , Colesterol/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/metabolismo , RNA Mensageiro/metabolismo , Interleucina-1/metabolismo
19.
J Biol Chem ; 299(11): 105325, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37805141

RESUMO

In multicellular organisms, a variety of lipid-protein particles control the systemic flow of triacylglycerides, cholesterol, and fatty acids between cells in different tissues. The chemical modification by oxidation of these particles can trigger pathological responses, mediated by a group of membrane proteins termed scavenger receptors. The lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor binds to oxidized low-density lipoprotein (oxLDL) and mediates both signaling and trafficking outcomes. Here, we identified five synthetic proteins termed Affimers from a phage display library, each capable of binding recombinant LOX-1 extracellular (oxLDL-binding) domain with high specificity. These Affimers, based on a phytocystatin scaffold with loop regions of variable sequence, were able to bind to the plasma membrane of HEK293T cells exclusively when human LOX-1 was expressed. Binding and uptake of fluorescently labeled oxLDL by the LOX-1-expressing cell model was inhibited with subnanomolar potency by all 5 Affimers. ERK1/2 activation, stimulated by oxLDL binding to LOX-1, was also significantly inhibited (p < 0.01) by preincubation with LOX-1-specific Affimers, but these Affimers had no direct agonistic effect. Molecular modeling indicated that the LOX-1-specific Affimers bound predominantly via their variable loop regions to the surface of the LOX-1 lectin-like domain that contains a distinctive arrangement of arginine residues previously implicated in oxLDL binding, involving interactions with both subunits of the native, stable scavenger receptor homodimer. These data provide a new class of synthetic tools to probe and potentially modulate the oxLDL/LOX-1 interaction that plays an important role in vascular disease.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores Depuradores Classe E , Humanos , Receptores Depuradores Classe E/genética , Receptores Depuradores Classe E/química , Receptores Depuradores Classe E/metabolismo , Células HEK293 , Lipoproteínas LDL/metabolismo , Receptores Depuradores/metabolismo , Lectinas/metabolismo
20.
Biomol Biomed ; 23(5): 815-824, 2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37669449

RESUMO

The same viral infection in different hosts may result in varying levels of clinical symptoms, which is related to the genetic background of the host itself. A total of 406 common cases and 452 severe cases of enterovirus 71 (EV71) infection in Yunnan Province were selected as the research subjects, and SNaPshot technology was used to detect genetic polymorphisms for 25 Tag single-nucleotide polymorphisms (TagSNPs) in the selectin P ligand (SELPLG) and scavenger receptor class B member 2 (SCARB2) genes. Our results demonstrate that SCARB2 polymorphisms (rs74719289, rs3733255 and rs17001551) are related to the severity of EV71 infection (A vs G: OR 0.330; 95% CI 0.115 - 0.947; T vs C: OR 0.336; 95% CI 0.118 - 0.958; and A vs G: OR 0.378; 95% CI 0.145 - 0.984). The SELPLG polymorphisms were not significantly different between common cases and severe cases. Therefore, we conclude that the SCARB2 gene has a protective effect on the course of hand, foot and mouth disease caused by EV71 infection and that SCARB2 gene mutations can reduce the severity of the disease.


Assuntos
Infecções por Enterovirus , Doença de Mão, Pé e Boca , Humanos , China , Patrimônio Genético , Polimorfismo de Nucleotídeo Único , Receptores Depuradores
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