• OxLDL
• SCARF1
• human
• lipoproteins
• low-density lipoproteins
• molecular biophysics
• scavenger receptor
• structural biology

• Humans
• Scavenger Receptors, Class F/metabolism
• Scavenger Receptors, Class F/chemistry
• Scavenger Receptors, Class F/genetics
• Protein Binding
• Crystallography, X-Ray
• Lipoproteins/metabolism
• Lipoproteins/chemistry
• Lipoproteins/genetics
• Protein Conformation
• Lipoproteins, LDL/metabolism
• Binding Sites
• Models, Molecular

• 91957102 National Natural Science Foundation of China
• SHSMU-ZLCX20212601 Innovative Research Team of High-level Local Universities in Shanghai

• Cancer
• Macrophages
• SR-A1
• SR-E3
• Therapy

• Animals
• Humans
• Disease Progression
• Macrophages/metabolism
• Mannose Receptor
• Mannose-Binding Lectins/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Cell Surface/metabolism
• Scavenger Receptors, Class A/metabolism

• antiviral therapy
• immune response
• scavenger receptors
• viral infection

• scavenger receptors
• macrophages
• liver sinusoidal endothelial cells
• cirrhosis
• hepatocellular carcinoma

• Atherosclerosis/etiology
• Hepatitis
• Humans
• Inflammation
• Neoplasms
• Receptors, Scavenger/metabolism

• Wellcome Trust
• 29959 Cancer Research UK
• C53575/A29959 Cancer Research UK

• ACE-2
• Immunity
• PAMPs
• Scavenger receptors
• Signalling pathways

Scavenger receptor class F member 1 (SCARF1) is thought to play an important role in the selective recruitment of CD4⁺ T cells to liver sinusoidal endothelial cells during chronic liver disease. However, the contribution of SCARF1 to hepatocellular carcinoma (HCC) is currently unknown. We utilized publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to explore SCARF1 expression in HCC and correlated it with a number of clinicopathological features. Flow adhesion assays were used to determine the role of SCARF1 in CD4⁺ T cell subset recruitment. SCARF1 expression was downregulated in HCC tumor tissues, compared to non-tumoral tissues, and loss of SCARF1 expression was associated with poorly differentiated/aggressive tumors. Additionally, higher SCARF1 expression in HCC tumor tissues was highly prognostic of better overall, disease-free and progression-free survival. SCARF1 within HCC was largely associated with tumor endothelial cells and adhesion studies suggested that it played a role in the specific recruitment of proinflammatory CD4⁺ T cells (CD4⁺CD25⁻) to HCC tumor tissues. Endothelial SCARF1 expression in tumor biopsies may provide critical prognostic information. Additionally, SCARF1 may also be a novel endothelial target that could help re-programme the microenvironment of HCC by promoting effector T cell tumor infiltration.

• leukocyte recruitment
• liver cancer
• scavenger receptor
• tumor endothelial cells
• tumor microenviroment

The scavenger receptor SR-F1 binds to and mediates the internalization of a wide range of ligands, and is involved in several immunological processes. We produced recombinant SR-F1 ectodomain and fragments deleted from the last 2 or 5 C-terminal epidermal growth factor-like modules and investigated their role in the binding of acetylated low density lipoprotein (AcLDL), complement C1q, and calreticulin (CRT). C1q measured affinity was in the 100 nM range and C1q interaction occurs via its collagen-like region. We identified two different binding regions on SR-F1: the N-terminal moiety interacts with C1q and CRT whereas the C-terminal moiety binds AcLDL. The role of SR-F1 N-linked glycans was also tested by mutating each of the three glycosylated asparagines. The three mutants retained binding activities for both AcLDL and C1q. A stable THP-1 cell line overexpressing SR-F1 was generated and C1q was shown to bind more strongly to the surface of SR-F1 overexpressing macrophages, with C1q/SR-F1 colocalization observed in some membrane areas. We also observed a higher level of CRT internalization for THP-1 SR-F1 cells. Increasing SR-F1 negatively modulated the uptake of apoptotic cells. Indeed, THP-1 cells overexpressing SR-F1 displayed a lower phagocytic capacity as compared with mock-transfected cells, which could be partially restored by addition of C1q in the extracellular milieu. Our data shed some light on the role of SR-F1 in efferocytosis, through its capacity to bind C1q and CRT, two proteins involved in this process.

• SPR
• apoptosis
• complement C1q
• interaction
• phagocytosis
• scavenger receptor SR-F1

• anticancer vaccine
• cancer immunotherapy
• combination immunotherapy
• dendritic cell targeting
• dendritic cell vaccine
• dendritic cells

Heat shock proteins (HSP) are a highly abundant class of molecular chaperones that can be released into the extracellular milieu and influence the immune response. HSP release can occur when cells undergo necrosis and exude their contents. However, HSPs are also secreted from intact cells, either in free form or in lipid vesicles including exosomes to react with receptors on adjacent cells. Target cells are able recognize extracellular HSPs through cell surface receptors. These include scavenger receptors (SR) such as class E member oxidized low-density lipoprotein receptor-1 (LOX-1, aka OLR1, Clec8A, and SR-E1) and scavenger receptor class F member 1 (SCARF1, aka SREC1). Both receptors are expressed by dendritic cells (DC) and macrophages. These receptors can bind HSPs coupled to client binding proteins and deliver the chaperone substrate to the pathways of antigen processing in cells. SR are able to facilitate the delivery of client proteins to the proteasome, leading to antigen processing and presentation, and stimulation of adaptive immunity. HSPs may also may be involved in innate immunity through activation of inflammatory signaling pathways in a mechanism dependent on SR and toll-like receptor 4 (TLR4) on DC and macrophages. We will discuss the pathways by which HSPs can facilitate uptake of protein antigens and the receptors that regulate the ensuing immune response.

• dendritic
• heat shock proteins
• immunity
• macrophage
• scavenger receptor

Scavenger receptors are a highly diverse superfamily of proteins which are grouped by their inherent ability to bind and internalize a wide array of structurally diverse ligands which can be either endogenous or exogenous in nature. Consequently, scavenger receptors are known to play important roles in host homeostasis, with common endogenous ligands including apoptotic cells, and modified low density lipoproteins (LDLs); additionally, scavenger receptors are key regulators of inflammatory diseases, such as atherosclerosis. Also, as a consequence of their affinity for a wide range of microbial products, their role in innate immunity is also being increasingly studied. However, in this review, a secondary function of a number of endothelial-expressed scavenger receptors is discussed. There is increasing evidence that some endothelial-expressed scavenger receptors are able to directly bind leukocyte-expressed ligands and subsequently act as adhesion molecules in the trafficking of leukocytes in lymphatic and vascular tissues. Here, we cover the current literature on this alternative role for endothelial-expressed scavenger receptors and also speculate on their therapeutic potential.

• LOX-1
• SCARF1
• SR-AI
• SR-PSOX
• leukocyte adhesion cascade
• mannose receptor
• stabilin-1
• stabilin-2

• Innate immune response
• microbial pathogenesis
• pathogens
• scavenger receptors

• Innate immunity
• Leukocyte adhesion molecule
• SCARF1
• SREC-I

Esophageal cancer-related gene 4 (Ecrg4) encodes a hormone-like peptide that is believed to be involved in a variety of physiological phenomena, including tumour suppression. Recent progress in the study of Ecrg4 has shown that Ecrg4 is a proinflammatory factor and induces the expression of several cytokines and chemokines in macrophages/microglia. However, the detailed molecular mechanisms of Ecrg4 signalling, especially the Ecrg4 receptors, remain poorly understood. Here, using retrovirus-mediated expression cloning, we identified lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) as a membrane protein that binds amino acid residues 71–132 of Ecrg4 (Ecrg4(71–132)). Moreover, in addition to LOX-1, several scavenger receptors, such as Scarf1, Cd36 and Stabilin-1, facilitated the efficient internalisation of Ecrg4(71–132) into cells. A broad competitive inhibitor of scavenger receptors, polyinosinic acid, reduced both the binding of Ecrg4(71–132) and the activation of NF-κB in microglia. This activation was dependent on MyD88, an adaptor protein that recruits signalling proteins to Toll-like receptors (TLRs), with the consequent induction of various immune responses. These data suggest that multiple scavenger receptors recognise Ecrg4(71–132) and transduce its signals, together with TLRs, in microglia.

Liver-resident cells are constantly exposed to gut-derived antigens via portal blood and, as a consequence, they express a unique repertoire of scavenger receptors. Whilst there is increasing evidence that the gut contributes to chronic inflammatory liver disease, the role of scavenger receptors in regulating liver inflammation remains limited. Here, we describe for the first time the expression of scavenger receptor class F, member 1 (SCARF-1) on hepatic sinusoidal endothelial cells (HSEC). We report that SCARF-1 shows a highly localised expression pattern and co-localised with endothelial markers on sinusoidal endothelium. Analysis of chronically inflamed liver tissue demonstrated accumulation of SCARF-1 at sites of CD4⁺ T cell aggregation. We then studied the regulation and functional role of SCARF-1 in HSEC and showed that SCARF-1 expression by HSEC is regulated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS). Furthermore, SCARF-1 expression by HSEC, induced by proinflammatory and gut-derived factors acts as a novel adhesion molecule, present in adhesive cup structures, that specifically supports CD4⁺ T cells under conditions of physiological shear stress. In conclusion, we show that SCARF-1 contributes to lymphocyte subset adhesion to primary human HSEC and could play an important role in regulating the inflammatory response during chronic liver disease.

• Staphylococcus aureus
• nasal colonization

Scavenger receptor expressed by endothelial cell-I (SREC-I) is a class F scavenger receptor expressed by immune cells with a significant role in CD8⁺- and CD4⁺-mediated T cell immunity. This receptor can also modulate the function of toll-like receptors (TLRs), which play essential roles in innate immunity. Earlier, it was found that human monocyte/macrophage THP1 cells and bone marrow-derived macrophages from mice exhibited increased responses to polyinosine–polycytidylic acid (poly I:C, PIC) and CpG (unmethylated) DNA and enhanced production of inflammatory cytokines with overexpressed SREC-I. Our data also showed that intracellular/endocytic TLR3 and TLR9 could directly interact with SREC-I in the presence of their respective ligands. We also observed that the internalized ligand along with TLR3/TLR9 colocalized in the endosome in macrophages and THP-1 cells overexpressing these receptors. In the absence of these ligands, there was no detectable colocalization between the SREC-I and endocytic TLRs. Earlier, it was shown that SREC-I stimulated double-stranded RNA/CpGDNA-mediated TLR3/TLR9 activation of the innate immune response by triggering signaling through the NF-κB, IRF3, and MAP kinase pathways leading to transcription of cytokine genes. We also established that SREC-I can associate with plasma membrane TLRs, such as TLR2 and TLR4. We demonstrated that SREC-I–TLR4 signals more efficiently from lipid microdomain in which lipopolysaccharide (LPS) can associate with SREC-I–TLR4 complex. We also proved that SREC-I is an alternate receptor for LPS capable of internalizing the complex and for endocytic TLR ligands as well. This binding activated endocytic TLR-mediated downstream cytokine production in THP1 cells and macrophages. Finally, SREC-I could also form complexes with TLR2 and induce the release of cytokines in the presence of bacterial, viral, and fungal ligands.

• SREC-I
• TLR3
• TLR4
• adaptive immunity
• innate immunity

Infection by hepatitis C virus (HCV), a plus-stranded RNA virus that can cause cirrhosis and hepatocellular carcinoma, is one of the major health problems in the world. HCV infection is considered as a multi-step complex process and correlated with abnormal metabolism of lipoprotein. In addition, virus attacks hepatocytes by the initial attaching viral envelop glycoprotein E1/E2 to receptors of lipoproteins on host cells. With the development of HCV model system, mechanisms of HCV cell entry through lipoprotein uptake and its receptor have been extensively studied in detail. Here we summarize recent knowledge about the role of lipoprotein receptors, scavenger receptor class B type I and low-density lipoprotein receptor in the entry of HCV, providing a foundation of novel targeting therapeutic tools against HCV infection.

• Lipoprotein receptors
• CD81
• Scavenger receptor class B type I
• Hepatitis C virus entry
• Low-density lipoprotein receptor

• Cancer immunotherapy
• Dendritic cells
• Scavenger receptor
• Tumor immunity
• Tumor-associated macrophage

• Animals
• Humans
• Neoplasms/diagnosis
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• Receptors, Scavenger/immunology
• Receptors, Scavenger/metabolism

• R01 CA099326 NCI NIH HHS
• R01 CA129111 NCI NIH HHS
• P30CA16059 NCI NIH HHS
• CA154708 NCI NIH HHS
• CA099326 NCI NIH HHS
• R01 CA175033 NCI NIH HHS
• R01 CA154708 NCI NIH HHS
• P30 CA016059 NCI NIH HHS
• CA175033 NCI NIH HHS

Scavenger receptor associated with endothelial cells I (SREC-I) was shown to be expressed in immune cells and to play a role in the endocytosis of peptides and antigen presentation. As our previous studies indicated that SREC-I required intact Toll-like receptor 4 (TLR4) expression for its functions in tumor immunity, we examined potential interactions between these two receptors. We have shown here that SREC-I became associated with TLR4 on binding bacterial lipopolysaccharides (LPS) in RAW 264.7 and HEK 293 cells overexpressing these two receptors. The receptors then became internalized together in intracellular endosomes. SREC-I promoted TLR4-induced signal transduction through the NF-kB and MAP kinase pathways, leading to enhanced inflammatory cytokine release. Activation of inflammatory signaling through SREC-I/TLR4 complexes appeared to involve recruitment of the receptors into detergent-insoluble, cholesterol-rich lipid microdomains that contained the small GTPase Cdc42 and the non-receptor tyrosine kinase c-src. Under conditions of SREC-I activation by LPS, TLR4 activity required Cdc42 as well as cholesterol and actin polymerization for signaling through NF-kB and MAP kinase pathways in RAW 264.7 cells. SREC-I appeared to respond differently to another ligand, the molecular chaperone Hsp90 that, while triggering SREC-I-TLR4 binding caused only faint activation of the NF-kB pathway. Our experiments therefore indicated that SREC-I could bind LPS and might be involved in innate inflammatory immune responses to extracellular danger signals in RAW 264.7 cells or bone marrow-derived macrophages.

• Animals
• Cytokines/immunology
• HEK293 Cells
• HeLa Cells
• Humans
• Inflammation Mediators/immunology
• Lipopolysaccharides/immunology
• Membrane Microdomains/immunology
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases/immunology
• NF-kappa B/immunology
• RAW 264.7 Cells/immunology
• Receptors, Scavenger/immunology
• Signal Transduction
• Toll-Like Receptor 4/immunology

• R01 CA047407 NCI NIH HHS
• R01 CA176326 NCI NIH HHS
• NIHRO1CA176326-01 NCI NIH HHS
• R01 CA119045 NCI NIH HHS
• NIHRO1CA119045 NCI NIH HHS
• NIHRO1CA47407-25 NCI NIH HHS

• Antigen cross presentation
• Immunity
• SREC-I
• Scavenger receptor

• Cancer
• dendritic cells
• heat-shock proteins
• infectious disease
• vaccines

• Adaptive Immunity
• Animals
• Bacterial Vaccines/immunology
• Bacterial Vaccines/metabolism
• Cancer Vaccines/immunology
• Cancer Vaccines/metabolism
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Heat-Shock Proteins/immunology
• Heat-Shock Proteins/metabolism
• Humans
• Immunity, Innate
• Lymphocyte Activation
• Receptors, Cell Surface/metabolism
• T-Lymphocytes/immunology
• Vaccines, Synthetic/immunology
• Viral Vaccines/immunology
• Viral Vaccines/metabolism

• srec-i
• gp2
• dendritic cell
• thp
• internalization
• acldl

• Animals
• Antibodies/immunology
• Antibodies/pharmacology
• Cell Line, Tumor
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Endocytosis/immunology
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Humans
• Mice
• Protein Binding/drug effects
• Protein Binding/physiology
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Scavenger Receptors, Class F/genetics
• Scavenger Receptors, Class F/immunology
• Scavenger Receptors, Class F/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Transduction, Genetic

• P 20508 Austrian Science Fund FWF