Therapeutic Applications of Nucleic Acids and Their Analogues in Toll-like Receptor Signaling

Abstract

Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from microbial components. Upon infection, nucleic acid sensing TLRs signal within endosomal compartment triggering the induction of essential proinflammatory cytokines and type I interferons to initiate innate immune responses thereby leading to a critical role in the development of adaptive immune responses. Thus, stimulation of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, allergies, malignant neoplasms and autoimmunity. This review summarizes the therapeutic applications of nucleic acids or nucleic acid analogues through the modulation of TLR signaling pathways.

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

“…These transcription factors play key roles in regulating the expression of adherent and costimulatory molecules and regulating the production of different cyto-kines such as TNF-a, IL-1b, IL-6, IL-12, IL-23, and type I IFNs, which are crucial for the maturation, differentiation, and proliferation of dendritic cells (DCs), NK cells, and cytotoxic T cells. Because these immune responses promote the killing of virusinfected cells and tumor cells, TLR7-9 agonists are being investigated for their applications as vaccine adjuvants and for their uses in the treatment of various infectious diseases and cancers (19)(20)(21).…”

Preconditioning with Intravenous Colitic Cell-Free DNA Prevents DSS-Colitis by Altering TLR9-Associated Gene Expression Profile

“…TLRs, widely expressed on different cells of the gastrointestinal epithelium and lamina propria [30], seem to be the sentinels of innate immunity being able to recognize several, mainly pathogen-derived or damaged host-cell-related antigenic structures, i.e., the pathogen-associated molecular patterns (PAMPs), and the danger-associated molecular patterns (DAMPs), respectively. Within the TLR family, TLR9 is stimulated notably upon sequence-and methylation-dependent DNA signaling [8]. Self-DNAs and oligonucleotides containing unmethylated CpG motifs are also senzed by and activate TLR9 [8].…”

“…Within the TLR family, TLR9 is stimulated notably upon sequence-and methylation-dependent DNA signaling [8]. Self-DNAs and oligonucleotides containing unmethylated CpG motifs are also senzed by and activate TLR9 [8].…”

“…It is conceivable that fcDNA may have a more active and widespread biological function than being a simple biomarker for screening, diagnosis or prognosis. Since the methylation status of fcDNA can be disease-and organ specific [51,52], and TLR9 is able to bind CpG-DNA sequences [8], application of modified DNA sequences is likely to represent a possible therapeutic alternative. Indeed, in patients with ulcerative colitis, there is an ongoing phase III clinical trial analyzing the local immunomodulatory capacity of a synthetic DNA-based immunomodulatory sequence (DIMS0150) [23].…”

“…Nucleic acids derived from microbial components are specifically senzed by intracellular TLRs (TLR3, 7,8,9) [8]. TLR9-expressing cells in the colonic mucosa [9,10] usually accumulate within the area of isolated lymphoid follicles (ILFs) and lymphoid aggregates (LAs) [11].…”