Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways

Abstract

Innate immunity, which is the first line of host defense against invading microbial pathogens in multicellular organisms, occurs through germline-encoded pattern-recognition receptors. The Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily comprises proteins that contain the phylogenetically conserved Toll/IL-1 receptor (TIR) domain, which is responsible for the propagation of downstream signaling through recruitment of TIR domain containing cytosolic adaptor proteins such as MyD88, TIRAP/MAL, TRIF, TRAM and SARM. These interactions activate transcription factors that regulate the expression of various proinflammatory cytokines (IL-1, IL-6, IL-8 and TNF-α) and chemokines. Activation of the TLR/IL-1R signaling pathway promotes the onset of inflammatory diseases, autoimmune diseases and cancer; therefore, this pathway can be used for the development of therapeutic strategies against these types of pathogenesis. In this review paper, we illustrate the role of the TIR-TIR domain interaction with the TLR/IL-1R signaling pathway in inflammation and apoptosis and recent therapeutic drugs targeted to inhibit the downstream signaling cascade for treatment of inflammatory diseases and cancer.

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

“…For example, TLRs couple ligand binding to conformational changes that are transduced through the plasma membrane to TIR domains in the cytosol and activate signaling pathways (37). The cytosolic adaptor TRIF/TICAM1 uses a mechanism wherein the N-terminal domain folds back onto the TIR domain to hide essential effector residues in the unstructured region adjacent to the TIR domain (30).…”

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

“…These kinases, in turn, through several additional signaling factors, lead to phosphorylation and degradation of the nuclear factor kB (NF-kB) inhibitor IkB and activation of the mitogen-activated protein kinase (MAPK) pathways involving extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 [ Fig. 2A; reviewed in (17)]. The final step in these direct signaling pathways involves translocation of activated transcription factors, such as activator protein 1 (AP-1) and NF-kB, to the nucleus, where they activate cell type-specific gene expression ( Fig.…”

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

“…[26][27][28] In the TRIF-dependent pathway, the TLR4 myeloid differentiation protein 2 (MD2)-LPS complex is internalized and transferred to early endosomes via TRIF-related adaptor molecule (TRAM), where TRAM, TRIF, TRAF3, TRAF6, and other adaptor proteins are recruited to activate NF-kB and interferon responses. [29][30][31] Activation of NF-kB, MAPK, and interferon results in enhanced inflammatory cytokine responses and induction of DCs function.…”