Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Abstract

Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-kappaB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.

Fig. 1

Toll-like receptor (TLR)-9 ligand cytosine (phosphodiester) guanine oligonucleotide (CpG-ODN 2084) (100 nM) induces rapid nuclear factor kappa-B (NF-κB) and activator protein-1 (AP-1) nuclear translocation as detected by electrophoretic mobility shift assay which can be inhibited by equimolar concentrations of inhibitory oligonucleotides (INH-ODNs) 2088 and 2114, but not with the control ODN 2310.

Fig. 2

Superior efficacy of class R INH-1, compared to class B inhibitor-18 (INH-18) in preventing renal damage in MRL-Fas^lpr/lpr mice. Periodic acid-Schiff (PAS) staining. Magnification: ×50 (upper panels); ×200 (lower panels).

Fig. 3

Class R inhibitor-1 (INH-1) completely, and class B INH-18 partially, restore resting B cell immunoglobulin (Ig)M⁺IgD⁺ phenotype in Murphy Roths large (MRL)-Fas^lpr/lpr mice. CD40⁺CD19⁺ gated splenic B cells were analysed for IgM and IgD expression in phosphate-buffered saline (PBS) or inhibitory oligonucleotide (INH-ODN)-treated MRL-Fas^lpr/lpr mice.