J Bacteriol Virol.  2011 Dec;41(4):225-235. 10.4167/jbv.2011.41.4.225.

Toll-like Receptors and Innate Immunity

• Yuk JM
• Jo EK

• KMID: 2168650
• DOI: http://doi.org/10.4167/jbv.2011.41.4.225

Abstract

Toll-like receptors (TLRs) are the best-characterized membrane-bound receptors in innate immune cells, including macrophages and dendritic cells. Upon recognition of specific ligands originating from pathogen- and modified self-derived molecules, TLRs trigger intracellular signaling cascades that involve various adaptor proteins and enzymes, resulting in the generation of proinflammatory and antimicrobial responses through the activation of transcription factors such as nuclear factor-kappaB. TLR-dependent signaling pathways are tightly regulated during innate immune responses by a variety of negative regulators. This review focuses on the newly described regulation of TLR-dependent signaling pathways, and emphasizes the roles of TLRs in innate immunity. Efforts to modulate these regulatory pathways and signaling molecules may result in the development of new therapeutic strategies through TLR-based therapy.

Keyword

Toll-like receptor; Nuclear factor-kappaB; Innate immunity

MeSH Terms

Dendritic Cells
Immunity, Innate
Ligands
Macrophages
Proteins
Toll-Like Receptors
Transcription Factors
Ligands
Proteins
Toll-Like Receptors
Transcription Factors

Figure

• 

  Figure 1. Toll-like receptor signaling pathways. Toll-like receptor (TLR) signaling is activated by stimulation of TLR ligands. TLR stimulation recruits MyD88 adaptor protein to the all TLRs except for TLR3. MyD88 interacts with a complex of the IRAKs and TRAF6 to activate the TAK1, which subsequently induces translocation of NF-κB and AP-1 to the nucleus through degradation of IκB proteins and activation of MAPKs, respectively. It leads to the expression of genes encoding the pro-inflammatory cytokines. Mal is also recruited to the TLR2/1, TLR2/6 and TLR4 to activate the MyD88-dependent pathway. TRIF protein is recruited to TLR3 and TLR4, which induces the interaction with a complex of TRAF3, TBK1 and IKKi to activate phosphorylation of IRF3. Activated IRF3 is dimerized and translocated into the nucleus, which induces protein expression of type I IFNs. TRIF also interacts with a TRAF6-RIP1 complex to activate NF-κB. TRAM is responsible for activation of TRIF-dependent pathway in TLR4, but not TLR3 signaling. Stimulation with ligands for TLR7, TLR8 and TLR9 forms a signaling complex consisting of MyD88, IRAK4, TRAF6, TRAF3, and IRAK1. TRAF6 and TRAF3 are responsible for activation of NF-κB (for proinflammatory cytokines) and IRF7 (for type I IFNs), respectively.

• 

  Figure 2. Negative regulators of Toll-like receptor signaling. Endogenous negative regulators inhibit excessive TLR signaling in diverse points. Soluble TLR2 and TLR4 function as competitors through inhibition of the interaction of TLR2 with ligand and formation of TLR4-MD2 complex, respectively. Both ST2L and SIGIRR are membrane-associated TLR regulators. ST2L binds to the MyD88 and MAL, whereas SIGIRR binds to TLR4, IRAK4 and TRAF6. Both of them inhibit MyD88-dependent pathway. Other intracellular TLR regulators include sMyD88, IRAKM, A20 and SHP: sMyD88 substitutes MyD88 to antagonize MyD88-dependent pathway through attenuation of IRAK4 recruitment; IRAKM inhibits IRAK1 phosphorylation by targeting IRAK1-IRAK4 complex; A20 is an inducible de-ubiquitination enzyme and de-ubiquitinylates TRAF6 to terminate TLR signaling; SHP functions as both a repressor of NF-κB and an inhibitor of TRAF6 ubiquitination.

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