Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation

Abstract

Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, including IMO-3100, IMO-8400, and CPG-52364, that block the interaction between endosomal TLRs and their ligands are under clinical investigation for their effectiveness in the treatment of psoriasis. In addition, several chemical compounds, including AS-2444697, PF-05387252, PF-05388169, PF-06650833, ML120B, and PHA-408, can inhibit TLR signaling. Although these compounds have demonstrated anti-inflammatory activity in animal models, their therapeutic potential for the treatment of psoriasis has not yet been tested. Recent studies demonstrated that natural compounds derived from plants, fungi, and bacteria, including mustard seed, Antrodia cinnamomea extract, curcumin, resveratrol, thiostrepton, azithromycin, and andrographolide, inhibited psoriasis-like inflammation induced by the TLR7 agonist imiquimod in animal models. These natural modulators employ different mechanisms to inhibit endosomal TLR activation and are administered via different routes. Therefore, they represent candidate psoriasis drugs and might lead to the development of new treatment options.

Figure 1

TLR ligands and signaling pathways. TLRs localize to the cell surface and to intracellular vesicles such as endosomes where they respond to their exogenous and endogenous ligands as shown. The TLRs utilize adaptor proteins of the MyD88 family, including MyD88, TRIF, TIRAP, and TRAM, to initiate downstream signaling pathways that induce the activation of various transcription factors, including NF-κB, AP-1, and IRF3/7, and the production of inflammatory cytokines and type I interferons.

Figure 2

Subfamilies and the extracellular structure of human TLRs. (a) Human TLRs are divided into three phylogenetic subfamilies shown with different colors. The number and cellular location of amino acid residues are shown in the middle and right columns, respectively. (b) Computational modeling of the ectodomain structure of dimerized TLR7. Blue color shows the horseshoe-shaped solenoid structure of TLR ectodomain. Arrowheads indicate undefined regions (red color).

Figure 3

The role of endosomal TLRs in the development of psoriasis and the mechanism of action of biological drugs. Endosomal TLRs in plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) can be triggered by self-DNA and self-RNA that forms complexes with LL37 upon its release from necrotic cells. Cytokines released by DCs further drive T cell-mediated inflammation by activating cytokines that promote leukocyte recruitment and keratinocyte activation and proliferation. Blue font: biological drugs inhibit effector cytokines in psoriatic inflammation.