Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics

Abstract

The recognition of invading pathogens and endogenous molecules from damaged tissues by toll-like receptors (TLRs) triggers protective self-defense mechanisms. However, excessive TLR activation disrupts the immune homeostasis by sustained pro-inflammatory cytokines and chemokines production and consequently contributes to the development of many inflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), infection-associated sepsis, atherosclerosis, and asthma. Therefore, inhibitors/antagonists targeting TLR signals may be beneficial to treat these disorders. In this article, we first briefly summarize the pathophysiological role of TLRs in the inflammatory diseases. We then focus on reviewing the current knowledge in both preclinical and clinical studies of various TLR antagonists/inhibitors for the prevention and treatment of inflammatory diseases. These compounds range from conventional small molecules to therapeutic biologics and nanodevices. In particular, nanodevices are emerging as a new class of potent TLR inhibitors for their unique properties in desired bio-distribution, sustained circulation, and preferred pharmacodynamic and pharmacokinetic profiles. More interestingly, the inhibitory activity of these nanodevices can be regulated through precise nano-functionalization, making them the next generation therapeutics or “nano-drugs.” Although, significant efforts have been made in developing different kinds of new TLR inhibitors/antagonists, only limited numbers of them have undergone clinical trials, and none have been approved for clinical uses to date. Nevertheless, these findings and continuous studies of TLR inhibition highlight the pharmacological regulation of TLR signaling, especially on multiple TLR pathways, as future promising therapeutic strategy for various inflammatory and autoimmune diseases.

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

“…For example, various TLRs have now also been implicated in the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and repair mechanism is brain disorders [496][497][498][499][500]. Thus, TLRs are playing an important role in infectious and non-infectious disease and are targeted as therapeutic approaches in these diseases [501,502]. Even studies have shown that these TLRs are controlling mammalian reproduction via regulating the process of steroidogenesis, spermatogenesis in males and ovulation, fertilization, gestation, and parturition in females [503][504][505][506].…”

Platelet TLR4 at the crossroads of thrombosis and the innate immune response

“…Small molecule inhibitors are synthetic or naturally derived chemical agents widely used in the drug industry. Because of their small size and amphipatic properties, small drugs are capable of crossing the cell membrane and act on specific intracellular targets …”

“…Because of their small size and amphipatic properties, small drugs are capable of crossing the cell membrane and act on specific intracellular targets. 56 Several small drugs have been shown to have inhibitory effects on the TLR4 pathways. For example, TAK-242 (Resatorvid) blocks the interaction between TLR4 and the adaptor proteins TIRAP and TRAM, leading to a reduction on TLR4 signaling and inflammation.…”

Concise Review: TLR Pathway-miRNA Interplay in Mesenchymal Stromal Cells: Regulatory Roles and Therapeutic Directions

“…Consequently, TLRs have been implicated in the pathogenesis of a range of conditions in which such an immune response is dysregulated. This makes them potential therapeutic targets in a variety of diseases, including cardiovascular disorders , inflammatory diseases such as rheumatoid arthritis and SLE , and GvHD . In fact, several agonists of TLR signaling (e.g., Imiquimod, Resiquimod, CpG‐ODN, PIC, and MPLA) have been evaluated in clinical trials for the treatment of various human diseases, including a wide range of malignancies, viral infections, and allergic conditions.…”