title: Scavenger receptor SREC-I promotes double stranded RNA-mediated TLR3 activation in human monocytes.
abstract: Scavenger receptor associated with endothelial cells (SREC-I) was previously shown to be expressed by immune cells and to play a role in CD8(+)-mediated T cell immunity. SREC-I was also shown to modulate the function of Toll like receptors with essential roles in innate immunity. Here we have shown that SREC-I enhanced double stranded RNA (dsRNA)-mediated Toll like receptor-3 (TLR3) activation. Viral double stranded RNA (dsRNA) was demonstrated to be a pathogen associated molecular pattern (PAMP) signaling viral infection. We found that in human monocyte/macrophage THP1 cells as well as murine bone marrow derived macrophages SREC-I led to elevated responses to the dsRNA-like molecule polyinosine-polycytidylic acid (Poly I:C) and enhanced production of inflammatory cytokines. Our data also showed that intracellular/endocytic TLR3 could directly interact with SREC-I in the presence of Poly I:C. The internalized ligand, along with TLR3 and SREC-I localized in endosomes within macrophages and in HEK293 cells engineered to express TLR3 and SREC-I. SREC-I also stimulated dsRNA-mediated TLR3 activation of signaling through the NFκβ, MAP kinase and interferon regulatory factor 3 (IRF3) pathways leading to expression of cytokines, most notably interleukin-8 and interferon-β. We therefore hypothesized that SREC-I could be a receptor capable of internalizing Poly I:C, boosting TLR3 mediated inflammatory signaling and stimulating cytokine production in macrophages.
authors: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors: Ayesha
authors: A
authors: Murshid
authors: Boston University Medical Center, United States.
authors: Jianlin
authors: J
authors: Gong
authors: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors: Ridwan
authors: R
authors: Ahmad
authors: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; School of Biosciences and Biomedical Research Institute, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
authors: Thiago J
authors: TJ
authors: Borges
authors: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States. Electronic address: scalderw@bidmc.harvard.edu.
authors: Stuart K
authors: SK
authors: Calderwood
mesh_terms: D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D011485:Protein Binding; D021381:Protein Transport; D012330:RNA, Double-Stranded / Q000378:metabolism*; D051128:Scavenger Receptors, Class F / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012330:RNA, Double-Stranded; C495126:SCARF1 protein, human; D051128:Scavenger Receptors, Class F; D051196:Toll-Like Receptor 3; D020928:Mitogen-Activated Protein Kinases; D011070:Poly I-C
keywords: Cytokines; Double stranded RNA; Poly I:C; SREC-I; THP1; TLR3
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