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.

Figure 1

Toll-like receptor signaling networks. TLR1,TLR2, TLR4, TLR5, and TLR6 work at the extracellular surface and TLR3, TLR7, TLR8, and TLR9 function in the endosomal/lysosomal compartments. The activation begins with the cytosolic TIR domains of receptor and adaptor proteins. Upon stimulation in MyD88-dependent pathways, MyD88 recruits IRAK4 through the death domain interactions. IRAK4 phosphorylates IRAK1, which associates with TRAF6. TRAF6 activates the TAK1protein associated with TAB1 and TAB2. TAK1 phosphorylates the IKK complex, thereby activating NF-κB subunits, which translocate to the nucleus. TAK1 also activatesMAPKs, resulting in the phosphorylation of JNKand p38, which finally culminate in the activation of AP-1. AP-1 and NF-κB induce proinflammatory cytokines such as IL-1, IL-12, and TNF-α. In MyD88-independent pathways, TRIF induces IFN-β and IFN-inducible genes through the activation of TRAF3. Stimulation of TLR7, TLR8, and TLR9 induces IRF7, leading to the production of typeI IFNs. MAL: MyD88-adaptor like, Ub: Ubiquitin.

Figure 2

TLR7 and TLR8-recognizing synthetic nucleoside analogues.