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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.

The immune system uses members of the toll-like receptor (TLR) family to recognize a variety of pathogen- and host-derived molecules in order to initiate immune responses. Although TLR-mediated, pro-inflammatory immune responses are essential for host defense, prolonged and exaggerated activation can result in inflammation pathology that manifests in a variety of diseases. Therefore, small molecule inhibitors of the TLR signaling pathway might have promise as anti-inflammatory drugs. We have previously identified a class of triaryl pyrazole compounds that inhibit TLR signaling by modulation of the protein-protein interactions essential to the pathway. We have now systematically examined the structural features essential for inhibition of this pathway, revealing characteristics of compounds that inhibited all TLRs tested (pan-TLR signaling inhibitors) as well as compounds that selectively inhibited certain TLRs. These findings reveal interesting classes of compounds that could be optimized for particular inflammatory diseases governed by different TLRs.

SARM (Sterile alpha and armadillo motif-containing protein) is the recently identified TIR domain-containing cytosolic protein. Classified as a member of the TLR adaptor family, the multiple locations and functions of SARM (sometimes playing opposing roles), provoke an enigma on its biology. Although originally assumed to be a member of the TLR adaptor family (functioning as a negative regulator of TLR signaling pathway), latest findings indicate that SARM regulates signaling differently from other TLR adaptor proteins. Recent studies have highlighted the significant functional role of SARM in mediating apoptosis and antiviral innate immune response. In this review, we provide an update on the evolutionary conservation, spatial distribution, and regulated expression of SARM to highlight its diverse functional roles. The review will summarize findings on the known interacting partners of SARM and provide analogy on how they add new dimensions to the current understanding on the multifaceted roles of SARM in antiviral activities and apoptotic functions. In addition, we provide a future perspective on the roles of SARM in differentiation and development, with substantial emphasis on the molecular insights to its mechanisms of action.

TLRs are crucial sensors of microbial infection. Maintaining structural integrity of TLR signaling components is essential for subsequent immunological protection. Alterations to the structure of these signaling molecules are often associated with profound clinical outcomes and susceptibility to various infectious diseases. These changes in structure are sometimes the result of a single nucleotide polymorphism (SNP). Numerous SNPs have been found in components of the TLR signaling pathway. Recently, the medical consequences and effects on TLR signaling of several of these SNPs have been elucidated. In addition, there have been numerous structures solved that are important to our understanding of the TLR signaling pathway at the molecular level. The scope of this review is to tie together current structural, biochemical, and genetic information of TLR signaling.

Toll-like receptors (TLRs) play a crucial role in the recognition of invading pathogens and the activation of subsequent immune responses against them. Individual TLRs recognize distinct pathogen-associated molecular patterns (PAMPs). The TLR family harbors an extracellular leucine-rich repeat (LRR) domain as well as a cytoplasmic domain that is homologous to that of interleukin-1 receptor (IL-1R). Upon stimulation, TLR recruits IL-1R-associated protein kinases via adaptor MyD88, and finally induces activation of nuclear factor-kappaB and mitogen-activated protein kinases. However, the response to TLR ligands varies, indicating the diversity of TLR signaling pathways. Besides MyD88, several novel adaptor molecules have recently been identified. Differential utilization of these adaptor molecules may provide the specificity in the TLR signaling. Characterization of each TLR signaling pathway will reveal the molecular mechanism of self-tolerance as well as cross-tolerance in response to a variety of PAMPs.

TLRs are primary sensors of invading pathogens, recognizing conserved microbial molecules and activating signaling pathways that are pivotal to innate and adaptive immune responses. However, a TLR signaling pathway must be tightly controlled because its excessive activation can contribute to the pathogenesis of many human diseases. This review provides a summary of the different mechanisms that are involved in the negative regulation of TLR signaling pathways.