Toll-like Receptor Signaling

Pathway Description:

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. They participate in the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, survival, and proliferation. To date, 11 members of the TLR family have been identified, of which TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are located on the cell surface and TLR3, TLR7, TLR8, and TLR9 are localized to the endosomal/lysosomal compartment. The activation of the TLR signaling pathway originates from the cytoplasmic Toll/IL-1 receptor (TIR) domain that associates with a TIR domain-containing adaptor, MyD88. Upon stimulation with ligands, MyD88 recruits IL-1 receptor-associated kinase-4 (IRAK-4) to TLRs through interaction of the death domains of both molecules. IRAK-1 is activated by phosphorylation and associates with TRAF6, thereby activating the IKK complex and leading to activation of MAP kinases (JNK, p38 MAPK) and NF-κB. Tollip and IRAK-M interact with IRAK-1 and negatively regulate the TLR-mediated signaling pathways. Additional modes of regulation for these pathways include TRIF-dependent induction of TRAF6 signaling by RIP1 and negative regulation of TIRAP-mediated downstream signaling by ST2L, TRIAD3A, and SOCS1. Activation of MyD88- independent pathways occurs via TRIF and TRAF3, leading to recruitment of IKKε/TBK1, phosphorylation of IRF3, and expression of interferon-β. TIR domain containing adaptors such as TIRAP, TRIF, and TRAM regulate TLR-mediated signaling pathways by providing specificity for individual TLR signaling cascades. TRAF3 plays a critical role in the regulation of both MyD88-dependent and TRIF-dependent signaling via TRAF3 degradation, which activates MyD88-dependent signaling and suppresses TRIF-dependent signaling (and vice versa).

Selected Reviews:

• Barton GM, Kagan JC (2009) A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat. Rev. Immunol. 9(8), 535–42.
• Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32(3), 305–15.
• Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11(5), 373–84.
• Lester SN, Li K (2014) Toll-like receptors in antiviral innate immunity. J. Mol. Biol. 426(6), 1246–64.
• Li X, Jiang S, Tapping RI (2010) Toll-like receptor signaling in cell proliferation and survival. Cytokine 49(1), 1–9.
• McGettrick AF, O'Neill LA (2010) Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr. Opin. Immunol. 22(1), 20–7.
• Miggin SM, O'Neill LA (2006) New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80(2), 220–6.
• Pasare C, Medzhitov R (2005) Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 11–8.
• Reuven EM, Fink A, Shai Y (2014) Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. Biochim. Biophys. Acta 1838(6), 1586–93.

We would like to thank Dr. Pranoti Mandrekar, University of Massachusetts Medical School, Worcester, MA, for contributing to this diagram.