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Pattern Recognition Receptors Pattern Recognition Receptors Pattern Recognition Receptors (Prrs) Are Select Pattern Recognition Receptor Agonists

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Pattern Recognition Receptors Pattern Recognition Receptors Pattern Recognition Receptors (Prrs) Are Select Pattern Recognition Receptor Agonists Pattern Recognition Receptors Pattern Recognition Receptors Pattern recognition receptors (PRRs) are Select Pattern Recognition Receptor Agonists essential for detecting invading pathogens Toll-like Receptors (TLRs) C-type Lectin Receptors (CLRs) and initiating the innate and adaptive TLRs Agonist(s) Source CLRs Agonist(s) Source immune response. There are multiple TLR1/ Triacyl lipopeptides Bacteria BDCA-2 Mannose, fucose Unknown families of PRRs including the membrane- TLR2 CLEC-1 Unknown Unknown associated Toll-like receptors (TLRs) and TLR2 Lipoproteins Multiple Pathogens C-type lectin receptors (CLRs), and the CLEC-2 Unknown Endogenous podoplanin Peptidoglycan (PGN) Bacteria (PDPN); HIV; Snake venom cytosolic NOD-like receptors (NLRs), RIG-I- Porins Bacteria protein rhodocytin like receptors (RLRs), and AIM2-like Zymosan Fungi CLEC4D/ Unknown Unknown CLECSF8 receptors (ALRs). PRRs are activated by b-Glycan Fungi specific pathogen-associated molecular CLEC9a Filamentous form Necrotic cells GPI-mucin Protozoa of actin patterns (PAMPs) present in microbial Envelope glycoproteins Viruses CLEC12B Unknown Unknown molecules or by damage-associated TLR2/ Diacyl lipopeptides Bacteria DCAR/ Unknown Unknown molecular patterns (DAMPs) exposed on the TLR6 CLEC4B Lipoteichoic acid (LTA) Bacteria surface of, or released by, damaged cells. In DCIR/ Mannose, fucose HIV TLR3 Double-stranded RNA Viruses CLEC4A most cases, ligand recognition by PRRs Poly (I:C) Synthetic analog of DC-SIGN/ High mannose, Candida albicans, triggers intracellular signal transduction double-stranded RNA CD209 fucose Cytomegalovirus, Dengue virus, filoviruses, HIV, cascades that result in the expression of TLR4 Lipopolysaccharide (LPS) Bacteria Leishmania spp., measles pro-inflammatory cytokines, chemokines, Glycoinositol- Protozoa virus, Mycobacterium spp., 1 phospholipids SARS, Schistosoma mansoni and antiviral molecules. In contrast, egg antigen Envelope glycoproteins Viruses activation of some ALRs and NLRs leads to Dectin-1/ b-1,3 glucans Fungi, mycobacteria Host-derived HMGB1 and Endogenous CLEC7A the formation of multiprotein inflammasome HSPs complexes that serve as platforms for the Dectin-2/ High mannose; Aspergillus fumigatus, TLR5 Flagellin Bacteria CLEC6A a-mannans Candida albicans, 2 Cryptococcus neoformans, cleavage and activation of Caspase-1. TLR7 Single-stranded RNA Viruses Caspase-1 promotes the maturation and Histoplasma capsulatum, TLR8 Single-stranded RNA Viruses Microsporum audouinii, secretion of IL-1b and IL-18, which further Mycobacterium tuberculosis, TLR9 Unmethylated CpG DNA Bacteria Paracoccidioides brasiliensis, amplifies the pro-inflammatory immune Saccharomyces cerevisiae, Protozoa response. Since a single pathogen can Trichophyton rubrum Viruses simultaneously activate multiple PRRs, LOX-1/ Oxidized low Endogenous; Bacteria; Also Mitochondrial DNA Endogenous OLR1 density lipoprotein activated by aged cells, crosstalk between different receptors may (ox-LDL); modified advanced glycation end TLR10 Unknown Unknown lipoproteins products, and HSP70 also play a role in enhancing or inhibiting MDL-1/ Unknown Dengue virus 3 the immune response. Therefore, tight CLEC5A regulation of PRR signaling is required in RIG-I-like Receptors (RLRs) MICL/ Unknown Unknown order to eliminate infectious pathogens and RLRs Agonist(s) Source CLEC12A Mincle/ a-mannose, Candida albicans, Malassezia Short 5' triphosphate at the same time, prevent aberrant or CLEC4E glycolipids, spp., Mycobacterium RIG-I single-stranded RNA containing Viruses SAP130 tuberculosis, dead cells excessive PRR activation, which can lead to some double-stranded regions (endogenous) the development of inflammatory and MDA5 Long double-stranded RNA Viruses SIGNR3/ High mannose, Mycobacterium tuberculosis 4 autoimmune disorders. RNA CD209d fucose LGP2 Unknown Viruses References 1. Takeuchi, O. & S. Akira (2010) Cell 140: 805. 2. Schroder, K. & J. Tschopp (2010) Cell 140:821. 3. Kingeter, L.M. & X. Lin (2012) Cell. Mol. Immunol. 9:105. 4. Mogensen, T.H. (2009) Clin. Microbiol. Rev. 22:240. Cover Illustration: A model of the ligand-bound TLR1/TLR2 heterodimer based on the crystal structure [Adapted from Jin, M.S. et al. (2007) Cell 130:1071.] NOD-like Receptors (NLRs) NOD-like Receptors (NLRs) NLRs Agonist(s) Source NLRs Agonist(s) Source NOD1 (NLRC1) Meso-diaminopimelic acid (Meso-DAP) Bacteria NLRP3/NALP3 Adenoviral DNA; Bacterial RNA; Candida albicans/Saccharomyces cerevisiae; Damage signals: Extracellular ATP, NAD+, b-amyloid, and NOD2 (NLRC2) Muramyl dipeptide (MDP) Bacteria particulates such as calcium pyrophosphate dihydrate and CIITA Unknown monosodium urate; Pore-forming toxins: Hemolysins, Listeriolysin O, Nigericin, Pneumolysin; Xenogenous compounds: Silica, asbestos, NAIP Legionella pneumophila; Flagellin (Naip5) alum, and uric acid; Influenza and Sendai virus RNA; Lipopolysaccharide (LPS); Klebsiella pneumoniae, Mycobacterium NLRC3 Unknown tuberculosis, Salmonella typhimurium, Schistosoma mansoni NLRC4 (IPAF) Legionella pneumophila; Pseudomonas aeruginosa; Salmonella NLRP4-14/NALP4-14 Unknown typhimurium; Shigella flexneri NLRX1 Unknown NLRC5 Unknown NLRP1/NALP1 Bacillus anthracis lethal toxin; Muramyl dipeptide (MDP) NLRP2/NALP2 Unknown 2 Learn more | rndsystems.com/prr Toll-like Receptors Toll-like receptors (TLRs) are a family of type I transmembrane pattern recognition receptors (PRRs) that are expressed by a number of different immune and non-immune cell types including monocytes, macrophages, dendritic cells, neutrophils, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.1 TLRs initiate the immune response following recognition of either conserved, pathogen-associated molecular patterns (PAMPs) present in microbial molecules or damaged-associated molecular patterns (DAMPs) present in molecules released by damaged cells. There are ten functional TLRs in humans and twelve in mice.2 Of the human TLRs, TLR1, 2, 4, 5, 6, and 10 are expressed on the cell surface and primarily recognize microbial membrane and/or cell wall components, while TLR3, 7, 8, and 9 are expressed in the membranes of endolysosomal compartments and recognize nucleic acids.3 TLRs have a variable number of ligand-sensing, leucine-rich repeats at their N-terminal ends and a cytoplasmic Toll/IL-1 R (TIR) domain. The TIR domain mediates interactions between TLRs and adaptor proteins involved in regulating TLR signaling including MyD88, TRIF, TRAM, and TIRAP/MAL. Signaling pathways activated downstream of these adaptor molecules promote the expression of pro-inflammatory cytokines, chemokines, and type I and type III interferons. As a result, additional immune cells are recruited to the infection site and pathogenic microbes and infected cells are eliminated. Although TLRs provide protection against a wide variety of pathogens, inappropriate or unregulated activation of TLR signaling can lead to chronic inflammatory and autoimmune disorders.4 References 1. Iwasaki, A. & R. Medzhitov (2004) Nat. Immunol. 5:987. 3. Blasius, A.L. & B. Beutler (2010) Immunity 32:305. 2. Kawai, T. & S. Akira (2011) Immunity 34:637. 4. Midwood, K.S. et al. (2009) Curr. Drug Targets 10:1139. TLR2/TLR6 TLR1/TLR2 TLR5 TLR4 TLR10 CD14 CD14 CD36 TLR2 Antibody (µg/mL) 10-2 10-1 100 CD14 TIRAP TIRAP 0.7 0.6 MD-2 MyD88 TIRAP MyD88 MyD88 TRAM Secretion (Mean O.D.) IL-8 MyD88 MyD88 0.6 0.5 TRIF 0.5 0.4 Antibody Endosome Lipopeptide TLR7 0.4 0.3 RIP1 IRAK4 IRAK1/2 TLR8 TLR9 TLR3 IL-8 Secretion (Mean O.D.) Secretion IL-8 0.3 0.2 TRAF-6 TAB1/2 TAK1 TRAF-6 MyD88 MyD88 TRIF 0.2 0.1 MyD88 10-2 10-1 100 TRAF-3 TRAF-3 Pam CSK (µg/mL) TANK 3 4 TLR2 Ligand-induced IL-8 Secretion and Neutralization IKK IRF7 using an Anti-Human TLR2 Antibody. The HEK293 human embryonic kidney cell line transfected with human TLR2 MKK RIP1 TBK1 was treated with increasing concentrations of the synthetic IKKε Proteasome TAB1/2 tri-palmitoylated lipopeptide Pam3CSK4. IL-8 secretion was IRF7 Homodimer TAK1 TRAF-6 measured using the Human CXCL8/IL-8 Quantikine® ELISA TRAF-3 Kit (Catalog # D8000C; gray line). The stimulatory effect IκB TANK Proteasome induced by 0.5 μg/mL Pam3CSK4 was neutralized by IKK treating the cells with increasing concentrations of a IκB IRF3 Mouse Anti-Human TLR2 Monoclonal Antibody (Catalog # NFκB MAB2616; purple line). JNK IκB MKK 40 p38 TBK1 IKKε IκB NFκB 30 p38 JNK IRF7 IRF3 Homodimer IRF3 20 IRF7 Homodimer IRF3 Homodimer Relative Cell Number Cell Relative 40 Domain Key 0 0 1 2 3 4 Leucine-Rich Repeat 10 10 10 10 10 TLR7 Domain (LRR) IRF3 NFκB AP-1 IRF7 NFκB AP-1 IRF3 or IRF7 Toll/IL-1 Receptor Intracellular Detection of TLR7 by Flow Cytometry. The Domain (TIR) Pro-inflammatory Cytokines: Ramos human Burkitt’s lymphoma cell line was stained Death Domain (DD) IL-1β, TNF-α, IL-6, IL-8, IL-18 with a PE-conjugated Mouse Anti-Human TLR7 Monoclonal Kinase Domain Type I or Type III IFN & IFN-inducible genes © 2012 R&D Systems, Inc. Antibody (Catalog # IC5875P; filled histogram) or a PE- conjugated Mouse IgG2A Isotype Control (Catalog # IC003P; open histogram). Learn more | rndsystems.com/tlr 3 C-type Lectin Receptors C-type lectin receptors (CLRs) are a diverse family of soluble and transmembrane proteins that contain one or more C-type lectin-like domain (CTLD). Multiple members of the CLR family are considered to be pattern recognition receptors (PRRs) due to their ability to recognize pathogen- associated molecules and induce intracellular signaling pathways that regulate the immune response. With the exception of DC-SIGN,
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