![]() ![]() ![]() Ligand stimulation recruits MyD88 and TIRAP to the TLR, and a complex of IRAKs and TRAF6 is subsequently formed. Lipoproteins and LPS are recognized on the cell surface by a heterodimer of TLR1/6 and TLR2, and by 2 sets of TLR4/MD2 complexes, respectively. Type I IFNs, including multiple forms of IFN-α and single forms of IFN-β, IFN-ω, etc., are also involved in the modulation of inflammation ( The complex that activates caspase-1, called the inflammasome, is composed of NLRs, ASC, and caspase-1 (see Review by K. Schroder and J. Tschopp on page 821 of this issue). However, IL-1β maturation requires cleavage of pro-IL-1β by a protease, caspase-1, which is activated independently of TLR signaling. The first step is the expression of an IL-1β zymogen, pro-IL-1β, which is regulated by the synthesis of its mRNA in a TLR signal-dependent manner. Although TNF and IL-6 are mainly regulated at the transcriptional and translational levels, the production of IL-1β is regulated by a two-step mechanism. These cytokines are pleiotropic proteins that regulate the cell death of inflammatory tissues, modify vascular endothelial permeability, recruit blood cells to inflamed tissues, and induce the production of acute-phase proteins. The inflammatory response is orchestrated by proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6. The expression patterns of the inducible genes differ among activated PRRs. These genes encode proinflammatory cytokines, type I interferons (IFNs), chemokines and antimicrobial proteins, proteins involved in the modulation of PRR signaling, and many uncharacterized proteins. With the exception of some NLRs, the sensing of PAMPs or DAMPs by PRRs upregulates the transcription of genes involved in inflammatory responses. These PRRs are expressed not only in macrophages and DCs but also in various nonprofessional immune cells. ![]() These families include transmembrane proteins such as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), as well as cytoplasmic proteins such as the Retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) and NOD-like receptors (NLRs). Currently, four different classes of PRR families have been identified. Recent evidence indicates that PRRs are also responsible for recognizing endogenous molecules released from damaged cells, termed damage-associated molecular patterns (DAMPs). ![]() They do this by recognizing structures conserved among microbial species, which are called pathogen-associated molecular patterns (PAMPs). Germline-encoded pattern recognition receptors (PRRs) are responsible for sensing the presence of microorganisms. Although innate immune cells including macrophages and dendritic cells (DCs) play important roles, nonprofessional cells such as epithelial cells, endothelial cells, and fibroblasts also contribute to innate immunity. Furthermore, innate immunity is also important for the activation of acquired immunity. ![]()
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