Scavenger receptor class‐A is a novel cell surface receptor for double‐stranded RNA

Abstract

Double-stranded RNA (dsRNA) is a potent signal to the host immune system for the presence of an ongoing viral infection. The presence of dsRNA, intracellularly or extracellularly, leads to the induction of innate inflammatory cytokines in many cell types including epithelial cells. However, the cell surface receptor for recognition of extracellular dsRNA is not yet determined. Here, we report that extracellular dsRNA is recognized and internalized by scavenger receptor class-A (SR-A). Treatment of human epithelial cells with specific antagonists of SR-A or with an anti-SR-A antibody significantly inhibited dsRNA induction of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and regulated on activation normal T-cell expressed and secreted (RANTES). Furthermore, intranasal dsRNA treatment of SR-A-deficient (SR-A(-/-)) mice showed a significant decrease in the expression of inflammatory cytokines and a corresponding decrease in the accumulation of polymorphonuclear leukocytes (PMNs) in lungs. These data provide direct evidence that SR-A is a novel cell surface receptor for dsRNA, and therefore, SR-A may play a role in antiviral immune responses.

The Human Antimicrobial Peptide LL-37, but Not the Mouse Ortholog, mCRAMP, Can Stimulate Signaling by Poly(I:C) through a FPRL1-dependent Pathway

“…7 and 8). These results further extend the previous observations of Limmon et al (32) and Itoh et al (24), who showed that poly(I:C) binds to Class A scavenger receptors and traffics to endosomes through clathrin-mediated endocytosis. The demonstration that poly(I:C)-LL-37 complexes enter cells using a different endocytic mechanism than poly(I:C) and the increased colocalization of the complex with TLR3 could provide a mechanism for LL-37 enhancing poly(I: C)-induced signaling by TLR3.…”

Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA

“…S5), PV5 likely utilizes the poly(I:C)/ODNuptake receptor for endocytosis. Although CD14 and the scavenger receptor class A were reported to act as a poly(I:C)-uptake receptor in mouse macrophages and human bronchial epithelial cells, respectively 42,43 , they did not participate in poly(I:C)/ODN cellular uptake in human DCs because of their absence on the cell surface 12 . There must be an additional uptake receptor for poly(I:C)/ODN.…”

Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth

“…This rapid time course of receptor phosphorylation is consistent with cell surface receptor activation, especially because we have shown that 21-nt siRNA is not internalized by these cells. Moreover, long dsRNAs, such as poly(I:C), which is internalized via scavenger receptors (7,29), effect much slower kinetics (Ϸ15-60 min) of phosphorylation (19,30). The baseline levels of TLR3 phosphorylation may be due to the presence of dsRNA from cell culture senescence or low levels of constitutive TLR3 dimerization.…”