25 Pathogenesis of sepsis DAMPs are heat shock proteins, fibrinogen, hyaluronic acid and high-mobility group box-1 protein (HMGB-1)[9]. Thus, PRRs recognize molecular components of both the pathogen (PAMPs) and the host (DAMPs), resulting in a vicious cycle and perpetuation of inflammation. Four main PRR families have been identified: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), Retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) and NOD-like receptors (NLRs)[7, 8]. TLRs comprise the most well-known family of PRRs [7]. They are expressed both extracellularly (TLR1, -2, -4, -5, -6) and intracellularly (TLR3, -7, -8, -9, -10, -11, -12, -13) in endosomes and lysosomes. Ten different TLRs have so far been identified in humans (TLR1 to -10); twelve are found in mice (TRL1 to -9, TLR11, -12, -13)[10]. TLRs are activated by a broad range of ligands presented by bacteria, viruses, parasites, fungi and the host itself. The signaling pathways of TLRs run via four adaptor proteins, namely myeloid differentiation primary-response protein 88 (MyD88), TIR-domain-containing-adaptorprotein (TIRAP), TIR-domain-containing-adaptor-protein-inducing-IFN-β (TRIF) and TRIF-related-adaptor-molecule (TRAM). This signaling eventually leads to the translocation of nuclear factor (NF-κB) into the nucleus which starts the transcoding of genes and is crucial for early activation of the immune system [8]. As an example of TLR signaling, TLR4 is stimulated through its ligand LPS, the virulence factor of gramnegative bacteria. It activates both the MyD88- and the TIRAP-dependent pathways for early-phase activation of NF-κB and results in late-phase activation of NF-κB via the TRIF-dependent pathway [7]. TLR3 is stimulated by dsRNA derived from viruses or virus-infected cells and activates the TRIF-dependent pathway [8]. NLRs are cytoplasmic proteins composed of a central nucleotide-binding domain and C-terminal leucine-rich repeats [11]. NLRs are an important factor in the initial immune response through their formation of multiprotein complexes called “inflammasomes”. These complexes activate caspase-1 leading to the maturation of proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 [12]. RLRs are cytoplasmic proteins that can recognize the genomic RNA of RNA viruses [13, 14]. CLRs are transmembrane receptors with a carbohydrate-binding domain. CLR-mediated microbial recognition occurs through their ability to recognize carbohydrates on viruses, bacteria and fungi (Table 1). 2
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