Bench-to-bedside review: Toll-like receptors and their role in septic shock

Abstract

The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader. The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions. These functional attributes of the cellular receptors provide insights into the nature of pattern recognition receptors that activate the human antimicrobial defense systems. The fundamental significance of the TLRs in the generation of systemic inflammation and the pathogenesis of septic shock is reviewed. The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

Figure 1

The homologies and interconnections between the Toll-like receptors (TLRs) and the type 1 interleukin-1 receptor (IL-1R1) complex. AcP, accessory protein; Ig, immunoglobulin; MyD88, myeloid differentiation factor; R, receptor; TIR, Toll/IL-1 receptor.

Figure 2

Comparisons between the signaling pathways in the insect and mammalian IL-1/Toll-like receptor (TLR) pathways. (d), Drosophilia homolog; ECSIT, evolutionarily conserved signaling intermediate of Toll; HSP, heat shock protein; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MEKK, mitogen-activated protein extracellular activated receptor kinase kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; TNF, tumor necrosis factor; TRAF6, tumor necrosis factor receptor-associated factor 6.

Figure 3

The intracellular signaling pathways of the Toll-like receptor 4 (TLR4) complex. IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; Mal, myeloid differentiation factor MyD88-like; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PKR, RNA binding protein kinase; TIR, Toll IL-1 receptor; TIRAP, Toll IL-1 receptor adapter protein; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.

Figure 4

The intracellular signaling pathways of the Toll-like receptor 2 (TLR2) complex. Akt, intracellular protein kinase; IKB, inhibitory subunit κB; IKK, I-κB kinase; IRAK, IL-1 receptor-associated kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, nuclear factor-κB inducing kinase; PG, peptidoglycan; PI3K, phosphatidyl inositol-3'-kinase; Rac, Rho-type GTPase; TIR, Toll IL-1 receptor; Tollip, Toll interactive protein; TRAF6, tumor necrosis factor receptor-associated factor 6.