What are the PRRs that recognize PAMPs
There are two broad categories of PRRs.
• Secreted PRRs and circulating PRRs: these include lectins, pentraxins, LPS-binding protein, collectins, and ficolins. Notable members of this group include:
• Mannan-binding lectin (MBL): synthesized in the liver as an acute phase protein, MBL binds microbial carbohydrates and initiates the lectin pathway of complement (see Question #8). MBL-associated serine proteases (MASP-2) function like C1r and C1s to activate the classical complement pathway. MBL deficiency is associated with frequent infections.
• C-reactive protein (CRP): as one of the pentraxin family members, CRP is also secreted as part of the acute phase response due to proinflammatory cytokines such as IL-6. CRP can fix C1q and activate complement to opsonize a pathogen for phagocytic clearance.
• Cell-associated PRRs.
• TLRs: there are at least 10 human TLRs. TLRs 1, 2, 4, 5, and 6 are on cell surfaces, whereas TLRs 3, 7, 8, 9, and 10 localize to endosomes. They individually recognize different PAMPs. For examples, TLR4 recognizes LPS and TLR5 recognizes flagellin, whereas TLR3 binds viral double-stranded RNA, TLR7/8 binds single-stranded RNA, and TLR9 binds CpG-DNA. Signaling through TLRs activates transcription factors (activator protein-1, nuclear factor-κB, interferon [IFN]-regulatory factors), resulting in induction of inflammatory and immune response genes with subsequent production of IFNs, proinflammatory cytokines (IL-1, IL-6, tumor necrosis factor [TNF]), chemokines (IL-8), and other effector cytokines that attract innate immune cells and direct the adaptive immune response.
• Intracellular PRRs: in addition to the endosomal localized TLRs, there are nucleotide oligomerization domain (NOD)-like receptors (NLRs) and retinoic acid-inducible gene (RIG)-I-like family receptors that reside in the cytoplasm.
• The NLRs include proteins NOD1 and NOD2 (also known as CARD15) and NOD leucine-rich repeat and pyrin domain containing (NLRPs). Upon PAMP binding to NLRs, an intracellular complex called the inflammasome forms, which contributes to the processing and secretion of IL-1 and IL-18. Urate crystals and peptidoglycans are examples of PAMPs that activate NLRs. Polymorphisms of NOD2 gene are associated with Crohn’s disease, and mutations in NLRPs have been associated with periodic fever syndromes.
• The RIG-I-like receptor family includes RIG 1, MDA5, LGP2. These receptors react with virus-derived double-stranded RNA and mediate the production of type-1 IFN.
• Receptors stimulating phagocytosis: macrophages and DCs have C-type lectin receptors that bind microbial carbohydrates. This includes the mannose receptor that binds bacterial carbohydrates and facilitates phagocytic clearance, cytokine release, and activation of immune cells. Dectin-1 is another C-type lectin receptor that binds fungal wall glucans. Mutations can lead to recurrent mucocutaneous fungal infections. Formyl peptide receptor is a G-coupled protein receptor on cells that binds N-formylmethionine from bacteria leading to release of chemoattractants, which facilitates phagocytosis. Finally, there are scavenger receptors on macrophages that facilitate removal of foreign substances by binding bacterial cell wall components, oxidized lipoproteins, and apoptotic cells.