The Scavenger Receptor SREC-I Cooperates with Toll-Like Receptors to Trigger Inflammatory Innate Immune Responses.

Ayesha Murshid,Benjamin J Lang,Stuart K Calderwood,Thiago J Borges

doi:10.3389/fimmu.2016.00226

Abstract

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.

Highlights

Scavenger receptors constitute a large family of protein molecules, which were identified by Brown and Goldstein in the year 1979 [1, 2]
We discuss how a member of scavenger receptor family F, scavenger receptor expressed by endothelial cell-I (SREC-I), cooperates with toll-like receptors (TLRs) and modulates its downstream signal activation in response to specific ligand stimulation
In the absence of known ligands, SREC-1 was shown to promote cell– cell homophilic interactions between murine fibroblast cells, an effect that was amplified upon coculture with SREC-II-expressing cells and negated by the Scavenger receptor expressed by endothelial cell-I (SREC-I) ligands AcLDL and oxidized low-density lipoprotein (ox-LDL) [9]. These findings identified a potential ligand-independent role for SREC-I in cell–cell interactions, a function possessed by other SRs, such as LOX-1, which was shown to facilitate leukocyte–endothelium adhesion [12]

Summary

Introduction

Scavenger receptors constitute a large family of protein molecules, which were identified by Brown and Goldstein in the year 1979 [1, 2]. We discuss how a member of scavenger receptor family F, scavenger receptor expressed by endothelial cell-I (SREC-I), cooperates with toll-like receptors (TLRs) and modulates its downstream signal activation in response to specific ligand stimulation. It was shown that HSP-chaperoned tumor antigen could be presented to both CD8+ and CD4+ T cells to activate immune response, which is known as T cell priming [14, 15].

Results

Conclusion