Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists

Abstract

Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases. This Perspective will highlight the recent discoveries in this field, emphasizing the role of TLRs in different diseases and the therapeutic effect of their natural and synthetic modulators, and it will discuss insights for the future exploitation of TLR modulators in human health.

Cytoplasmic‐translocated Ku70 senses intracellular DNA and mediates interferon‐lambda1 induction

“…Under the context of DNA virus infection, the innate immune system has to be able to detect DNA from pathogens in order to induce a strong antiviral innate immune response. 62 It is reported that DNA vaccination relies on DNA sensing to invoke a powerful innate immune response that, in turn, assists the adaptive response. 63 DNA can also act as a damage-associated molecular pattern (DAMP), accelerating inflammatory responses following its release from dying or damaged cells directly contributing to the pathogenesis of various diseases such as atherosclerosis 64 and deep vein thrombosis.…”

Medicinal Plants and Isolated Molecules Demonstrating Immunomodulation Activity as Potential Alternative Therapies for Viral Diseases Including COVID-19

“…Natural products are known to primarily stimulate the nonspecific immune responses (innate immunity), in which the mediators of immune system including cytokines, macrophages, neutrophils, acute-phase proteins and monocytes provide instant defense against pathogens ( 60 ). Pathogens express different factors known as pathogen-associated molecular patterns (PAMPs), which are recognized by the host to perceive the presence of pathogens.…”

“…PAMPs are recognized by host sensors using PRRs triggering a sequence of immune reactions through the generation of type-1 IFNs, cytokines, and chemokines. PRR families include NOD-like receptors, Toll-like receptors (TLRs), RIG-I-like receptors and DNA receptors ( 60 ). TLR-3, -7,- 8, and -9 are extremely important in sensing viral infections as they transduce signals to the system, which then activates antiviral processes.…”

“…TLR-3, -7,- 8, and -9 are extremely important in sensing viral infections as they transduce signals to the system, which then activates antiviral processes. Agents that nonspecifically stimulate TLR-mediated responses may be potential antiviral remedies ( 60 ). In nonspecific immunity, antigen-presenting cells (APCs) and macrophages play important roles in cytokine secretion, antibody-dependent cell-mediated cytotoxicity and antigen presentation, processing and phagocytosis.…”

The role of toll‐like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?

“…Upon TLR4 activation, two distinct adapter proteins are recruited to induce two parallel pathways and it is interesting to note that TLR4 is the only member of the TLR family that is able to activate both these pathways (Federico et al, 2020). For the first pathway, the TIRAP adapter binds to the TIR domain of the receptor and then recruits MyD88 that serves as one of the most important activator proteins connecting many signaling pathways in the cells.…”