Toll-like receptors: potential targets for lupus treatment

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN-α) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.

miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling

“…miR-15a is predicted to target TLR5/and 8, and the TLR signaling mediates the activation of NF-κB [18–20, 23, 24]. Additionally, TNFα is known to activate NF-κB [25, 26].…”

Dendritic cell recruitment and activation in autoimmunity

“…The concept of therapeutically targeting the activation of pDCs in SLE is historically vindicated by the beneficial effects of hydroxychloroquine, one mainstay of SLE treatment, that is now known to act mainly by reducing TLR activation [245]. Nowadays, the ascertained involvement of type I IFN production by pDCs in apparently distant pathologies such as SLE and T1D is paving the way to the design and testing new molecules focusing on depleting or inhibiting pDCs type I IFN-mediated autoimmune diseases (Table 1).…”

“…Among these, the quinazoline derivative CpG-52365, has completed a phase I clinical trial in SLE (ClinicalTrials. gov identifier NCT00547014) after having shown to be safer and more effective than hydroxychloroquine in preclinical animal studies [245]. Of course, all of these approaches are not pDC specific and may inhibit the activation of all TLR7/9-(and in some cases also TLR8) bearing cells, although the relative importance of other cell types in these diseases was demonstrated to be marginal.…”

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

“…TLR7 and TLR9 have been implicated in the pathophysiology of lupus (14). Some of the key characteristics of lupus include high levels of autoantibodies specific for nucleic acid and nucleic acid-binding proteins, as well as high expression of IFN-regulated genes by peripheral blood leukocytes (15).…”