Polyinosinic Acid Is a Ligand for Toll-like Receptor 3

Abstract

Innate immune responses are critical in controlling viral infections. Viral proteins and nucleic acids have been shown to be recognized by pattern recognition receptors of the Toll-like receptor (TLR) family, triggering downstream signaling cascades that lead to cellular activation and cytokine production. Viral DNA is sensed by TLR9, and TLRs 3, 7, and 8 have been implicated in innate responses to RNA viruses by virtue of their ability to sense double-stranded (ds) RNA (TLR3) or singlestranded RNA (murine TLR7 and human TLR8). Viral and synthetic dsRNAs have also been shown to be a potent adjuvant, promoting enhanced adaptive immune responses, and this property is also dependent on their recognition by TLR3. It has recently been shown that mRNA that is largely single-stranded is a ligand for TLR3. Here we have investigated the ability of single-stranded homopolymeric nucleic acids to induce innate responses by murine immune cells. We show for the first time that polyinosinic acid (poly(I)) activates B lymphocytes, dendritic cells, and macrophages and that these responses are dependent on the expression of both TLR3 and the adaptor molecule, Toll/IL-1 receptor domain-containing adaptor inducing IFN-␤ (TRIF). We therefore conclude that TLR3 is able to sense both single-stranded RNA and dsRNA.

Differential Modulation of TLR3- and TLR4-Mediated Dendritic Cell Maturation and Function by Progesterone

“…pp , 0.05 compared with stimulated controls using a MannWhitney U test. 41). We believe that our data demonstrate a further mechanism through which progesterone could be functioning to limit the antiviral response by reducing TLR3-induced inflammatory responses.…”

SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens

“…26 We utilized polyinosinic acid (polyI) a synthetic polyanionic ligand for SR-A/MARCO that also stimulates intracellular TLR3 to release inflammatory cytokines. 28 Similarly, the bacterial cell wall product muramyl dipeptide (MDP) stimulated the cytosolic sensor NOD2, and silica, asbestos, and a combination of NM and extracellular ATP stimulated NALP3 inflammasomes and engaged SR-A and MARCO. 29,30 We show that SR-A/MARCO competes with TLR4 for ligand recognition, limiting its inflammatory response, but strikingly enhances TLR3-, NOD2-, and NALP3-mediated inflammatory responses.…”

“…To investigate how SR-A and MARCO modulate the inflammatory response by intracellular TLR3, which signals independently of MyD88, we utilized polyI, a synthetic polyanionic ligand for SR-A, MARCO, and intracellular TLR3. 28 WT, SR-A Ϫ/Ϫ , MARCO Ϫ/Ϫ , and DKO macrophages were stimulated with polyI, and secretion of cytokines was measured. Results showed that polyI induced TNF-␣ and IL6 in WT M as expected, but cytokine secretion was almost completely abolished in SR-A Ϫ/Ϫ and DKO macrophages.…”

Opposing roles of RNA receptors TLR3 and RIG-I in the inflammatory response to double-stranded RNA in a Kaposi’s sarcoma cell line

“…In some cases, the mode of delivery, for example transfection versus addition to media, also influences the response [24], which may be due to effects on localization of the ligand within the cell as well as the amount of ligand taken up. TLR3 is commonly located in endosomes and recognizes double-stranded RNA and its mimic poly(I:C) [25], and more recently it was shown to also recognize single-stranded poly(I) [26]. RIG-I and MDA5 are cytoplasmic RNA helicases originally identified as double-stranded RNA receptors [10]; however, RIG-I was shown to recognize single-stranded RNA with 5′ triphosphates [27,28].…”