Targeting Negative Regulators of TRIF-dependent TLR Signaling Pathway as a Novel Therapeutic Strategy

Background: Toll-Like Receptors (TLRs) are a subclass of pathogen-associated molecular patterns (PAMPs). There is a growing interest in the use of TLR agonists for various pathological dysfunctions, including cancer, microbial infections, and inflammatory diseases. TLR3/4 agonists that can induce TIR-domain-containing adapter-inducing interferon-β (TRIF)- dependent pathway have shown fewer toxic immunostimulatory responses in comparison to other small molecules. Furthermore, TLR3 agonists indicate promising anti-tumor potential in cancer immunotherapy either as vaccine adjuvant or monotherapy. Objective: It is logical to assume that the induction of the genes that are involved in TRIF pathway to augment their pleiotropic effects on different cells via TLR agonists, could enhance the treatment process of disease while minimizing the toxicity related to using other small molecules. Methods: An extensive literature search to identify the negative regulators of TRIF-dependent signaling pathway and their biological functions was performed from two databases PubMed and Scopus. Results: Negative regulators of TRIF signaling pathways were identified. In addition, structure and function of sterile α- and armadillo-motif containing protein (SARM), the only TIR domaincontaining adaptor protein that inhibits TRIF-dependent activation, were briefly reviewed. Conclusion: We proposed that the manipulation of TRIF signaling pathway via targeting its negative regulators could be used as an approach to modulate the functions of this pathway without undesired toxic proinflammatory responses.