Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus

TLDR

Elevated interferon‑α levels in systemic lupus erythematosus correlate with disease activity and are thought to arise from activated plasmacytoid dendritic cells stimulated by DNA, RNA, or immune complexes containing self‑nucleic acids. The authors aimed to create oligonucleotide‑based inhibitors that block Toll‑like receptor signaling in systemic lupus erythematosus. They designed three series of ODN inhibitors targeting TLR9 alone, TLR7 alone, or both TLR7 and TLR9. The inhibitors selectively suppressed IFN‑α production by plasmacytoid dendritic cells in response to DNA or RNA viruses, confirming that mammalian DNA and RNA immune complexes activate TLR9 and TLR7 and that TLR signaling promotes lupus, thereby positioning these inhibitors as potential therapeutics.

Abstract

Raised serum levels of interferon (IFN)-α have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-α is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-α. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-α production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-α production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-α by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.