Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics

Abstract

The Toll-like receptor 4 (TLR4) signaling pathway plays a central role in the prompt defense against infectious challenge and provides immediate response to Gram-negative bacterial infection. The TLR4/MD-2 complex can sense and respond to various pathogen-associated molecular patterns (PAMPs) with bacterial lipopolysaccharide (LPS) being the most potent and the most frequently occurring activator of the TLR4-mediated inflammation. TLR4 is believed to be both a friend and foe since improperly regulated TLR4 signaling can result in the overactivation of immune responses leading to sepsis, acute lung injury, or pathologic chronic inflammation involved in cancer and autoimmune disease. TLR4 is also considered a legitimate target for vaccine adjuvant development since its activation can boost the adaptive immune responses. The dual action of the TLR4 complex justifies the efforts in the development of both TLR4 antagonists as antisepsis drug candidates or remedies for chronic inflammatory diseases and TLR4 agonists as vaccine adjuvants or immunotherapeutics. In this review, we provide a brief overview of the biochemical evidences for possible pharmacologic applications of TLR4 ligands as therapeutics and report our systematic studies on the design, synthesis, and immunobiological evaluation of carbohydrate-based TLR4 antagonists with nanomolar affinity for MD-2 as well as disaccharide-based TLR4 agonists with picomolar affinity for the TLR4/MD-2 complex.

Nrf2 orchestrates transition from acute to chronic otitis media through inflammatory macrophages

“…Second, Nrf2 interacts with toll-like receptor 4 (TLR4) signaling during inflammation (14). TLR4 is a TLR family member critical for innate immune response to infection (15). The TLR4 signaling pathway begins with the recognition of its ligand, which leads to the recruitment of adaptor proteins, such as MyD88 and TRIF, to the TLR4 complex (15).…”

“…TLR4 is a TLR family member critical for innate immune response to infection (15). The TLR4 signaling pathway begins with the recognition of its ligand, which leads to the recruitment of adaptor proteins, such as MyD88 and TRIF, to the TLR4 complex (15). These adaptors, in turn, activate downstream kinases, such as IRAK and TBK1, which phosphorylate and activate transcription factors, such as NF-kB and IRF3, respectively (15).…”

“…The TLR4 signaling pathway begins with the recognition of its ligand, which leads to the recruitment of adaptor proteins, such as MyD88 and TRIF, to the TLR4 complex (15). These adaptors, in turn, activate downstream kinases, such as IRAK and TBK1, which phosphorylate and activate transcription factors, such as NF-kB and IRF3, respectively (15). Activation of NF-kB leads to the expression of a wide range of pro-inflammatory cytokines, including TNFa, IL-1b, and IL-6, as well as chemokines, adhesion molecules, and other immune effector molecules (16).…”

Critical review on anti‐inflammation effects of saponins and their molecular mechanisms

“…It is important to note that the specific effects of saponins can vary depending on their chemical structure, source, and concentration. Additionally, the research in this area is ongoing, and the understanding of how saponins interact with TLR4 and modulate inflammation is still evolving (Heine & Zamyatina, 2023; Kuzmich et al, 2017). Examples of plants containing saponins with potential anti‐inflammatory properties include ginseng, licorice, and various legumes.…”

Adopting orphan receptors: group IX/X transition metals as potential ligands of zebrafish Tlr4 homologs

“…Toll-like receptors (TLRs) are evolutionarily ancient proteins with origins dating back to more than 700 MYA and can be found in a range of organisms from corals to humans (Behzadi et al, 2021; Fitzgerald & Kagan, 2020). Mammalian TLR4 is multifaceted in its function with involvement in pathogen recognition, cancer pathology, and autoimmune disease (Heine & Zamyatina, 2022). The best studied function of TLR4 in humans is its ability to detect and bind to microbial pathogen associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), and viral glycoproteins, which are essential for the body’s inflammatory response to pathogens.…”