Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

Abstract

Pathogens are sensed by pattern recognition receptors (PRRs), which are germ line-encoded receptors, including transmembrane Toll-like receptors (TLRs) and cytosolic nucleotide oligomerisation domain (NOD) proteins, containing leucine-rich repeats (NLRs). Activation of PRRs by specific pathogen-associated molecular patterns (PAMPs) results in genomic responses in host cells involving activation transcription factors and the induction of genes. There are now at least 10 TLRs in humans and 13 in mice, and 2 NLRs (NOD1 and NOD2). TLR signalling is via interactions with adaptor proteins including MyD88 and tollreceptor associated activator of interferon (TRIF). NOD signalling is via the inflammasome and involves activation of Rip-like interactive clarp kinase (RICK). Bacterial lipopolysaccharide (LPS) from Gram-negative bacteria is the beststudied PAMP and is activated by or 'sensed' by TLR4. Lipoteichoic acid (LTA) from Gram-positive bacteria is sensed by TLR2. TLR4 and TLR2 have different signalling cascades, although activation of either results in symptoms of sepsis and shock. This review describes the rapidly expanding field of pathogen-sensing receptors and uses LPS and LTA as examples of how these pathways parallel and diverge from each other. The role of pathogen-sensing pathways in disease is also discussed.

ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way

“…The entire set of PRRs is likely redundant, with extensive cross-talk and possibly positive or negative feedback controls (3). The idea of a large number of different sensors converging on relatively few signaling pathways, at least for a common inflammatory response such as IL-1␤ secretion, is supported by the observation that the same biochemical events previously identified as mediators of ATPinduced secretion [K ϩ eff lux (26), activation of calciumindependent (27) and calcium-dependent (9) PLA 2 , deacetylation events (28)] are involved in the secretion of mature IL-1␤ driven by engagement of all of the PRRs tested.…”

“…Microbial components, named pathogen-associated molecular patterns (PAMPs), and molecules released by injured tissues, called danger-associated molecular patterns (DAMPs), trigger pattern recognition receptors (PRRs) resulting in infectious and sterile inflammation, respectively (2)(3)(4).…”

“…PRRs include Toll-like receptors (TLRs, at least 10 in humans) and nucleotide oligomerization domain (NOD) proteins (NOD1 and NOD2) (3,13,14) that sense specifically different PAMPs. LPS from Gram-negative bacteria is the best-studied ligand for TLR4 (3), whereas Gram-positive bacteria preferentially activate TLR2 through lipoteichoic acid (15).…”

“…TLR2 and TLR6 are targets for the yeast wall component zymosan (15), whereas TLR5 is the extracellular receptor for bacterial flagellin (16). PAMPs able to gain access to the cytosol, like peptidoglycans, bind NOD proteins (2,3,14). Interestingly, muramyl dipeptide (MDP), a component of peptidoglycans, also binds the inflammasome components NALP3 (17) and NALP1 (18).…”

“…Interestingly, muramyl dipeptide (MDP), a component of peptidoglycans, also binds the inflammasome components NALP3 (17) and NALP1 (18). The different PRRs generate signaling cascades converging on similar effects on host cells, including induction of genes related to the inflammatory response (3,14) and inflammasome activation (19)(20)(21). Recently, it has been proposed that not only PAMPs, but also some DAMPs released by injured tissues, such as uric acid, are able to trigger IL-1␤ secretion (22).…”