Molecular and Cellular Interactions of Scavenger Receptor SR-F1 With Complement C1q Provide Insights Into Its Role in the Clearance of Apoptotic Cells

Abstract

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.

Prognostic Value and Potential Immunoregulatory Role of SCARF1 in Hepatocellular Carcinoma

“…Furthermore, SCARF1 is primarily a scavenger receptor, and so the impact of its presence with regards to its scavenging function also needs to be considered in future studies. SCARF1 has been shown to bind a range of endogenous ligands, such as oxidized lipoproteins (21), heat shock proteins (23)(24)(25) and apoptotic cells (26,27), and regulate LPS responses (35); therefore, all these functions could also potentially influence the tumor microenvironment. For example, the uptake of these factors by SCARF1 could prevent neutrophil and macrophage accumulation in the tumor microenvironment, thus providing an alternative mode-of-action for the anti-tumoral action of SCARF1, as myeloid cell accumulation is often associated with poor prognosis in HCC (63,64).…”

“…Scavenger receptor class F, member 1 (SCARF1 or SR-F1), also known as scavenger receptor expressed by endothelial cells (SREC)-I, was first identified in cDNA libraries from human umbilical vein endothelial cells (HUVEC) (20). SCARF1 has been shown to bind and internalize modified low density lipoproteins (LDLs), specifically acLDLs (21), and a wide range of other endogenous damage-associated products (22), such as heat-shock proteins (HSPs) (23)(24)(25) and apoptotic host cells (26,27). In addition to a diverse range of endogenous ligands, SCARF1 also binds a wide array of viral (28)(29)(30), fungal (31), and bacterial (32)(33)(34)(35) antigens.…”

Having an Old Friend For Dinner: The Interplay between Apoptotic Cells and Efferocytes

“…SCARF-1, previously known as "scavenger receptor expressed by endothelial cell 1" (SREC-1, SR-F1) is an ortholog to the C. elegans receptor CED-1 [89]. Unlike the receptors discussed thus far, SCARF-1 indirectly recognizes phosphatidylserine through the opsonin C1q [90,91]. SCARF-1's importance is highlighted by knockout studies revealing impaired apoptotic cell uptake and increased rates of autoimmunity [89].…”

“…Multiple integrins can recognize apoptotic cells and participate in efferocytosis, including αvβ5, αvβ3 and αxβ2. Integrins recognize apoptotic cells via the PtdSer opsonin milk fat globule-EGF-factor 8 (MFG-E8) [91,92,95]. MFG-E8 binds to PtdSer through its C2 domain [95], but also binds to other phospholipids exposed on the cell surface during apoptosis including phosphatidylethanolamine.…”

Exploring the prognostic value of SCARF1 in non-small cell lung cancers

“…SCARF1 was first identified in cDNA libraries from human umbilical vein endothelial cells (HUVEC) [21] and exhibits high expression in primary human liver sinusoidal endothelial cells (LSEC) [22], which are also known to be exposed to high levels of antigenic matter from the gut. SCARF1 has been shown to bind and internalise a wide range of endogenous and exogenous ligands [23], such as apoptotic host cells [24] and viral [25][26][27], fungal [19] and bacterial [28][29][30][31] antigens. Nevertheless, its expression in human lung tissues and in cancers of the lung have not been explored in any detail to date.…”