Pattern recognition receptors (PRRs) are used by phagocytic cells to identify potential pathogens. There are 3 broad categories of PRRs: free receptors, membrane-bound receptors, and cytoplasmic receptors.
Free Receptors
“Free” receptors refer to receptors found circulating in the blood, that are not attached to a specific cell. These receptors generally recognize microbial sugars. The most well-known of these receptors is mannose-binding lectin (MBL), which specifically recognizes lectin on bacterial pathogens. MBL has an important role in the lectin complement pathway, further discussed here. Another free receptor group that can activate complement are the ficolins, which bind acetylated sugars.
Membrane-Bound Receptors
The membrane-bound receptors have two groups: phagocytic and signalling receptors. These receptors have the functions suggested by their name!
Phagocytic Receptors
The phagocytic PRRs are found on macrophages and neutrophils, and primarily activate phagocytosis of bound proteins. The major phagocytic PRRs are dectin-1, mannose receptor and scavenger receptors. Dectin-1 specifically recognizes glucose polymers, which are often found in fungal cell walls. Similarly, mannose receptor recognizes mannose-containing sugars that can be found on bacteria, fungi and some viruses. Scavenger receptors recognize lipoproteins and collagen. The most well-known scavenger receptor is MARCO (macrophage receptor with a collagenous structure).
It is also important to note that macrophages and neutrophils have phagocytic receptors for complement fragments, to bind to microbes coated in complement proteins. The main receptor in this category is CR3.
Signalling Receptors
The signalling receptors induce production of cytokines by macrophages, which are the major signalling molecules of the immune system. By doing so, macrophages can activate an adaptive immune response. The main membrane-bound signalling receptors are Toll-like receptors (TLRs).
The TLRs are a very large family of receptors, with each TLR recognizing a specific PAMP. The ligands of some of the most important TLRs and the cellular location of these receptors is summarized below:
| TLR | Notable Ligands | Cellular Location |
|---|---|---|
| TLR2 | Lipoteichoic acid | Cell surface |
| TLR3 | dsRNA of viruses | Endosome |
| TLR4 | Lipopolysaccharide | Cell surface |
| TLR5 | Flagellin | Cell surface |
| TLR7 | ssRNA of RNA viruses | Endosome |
| TLR9 | CpG islands in DNA of viruses and bacteria | Endosome |
A brief note on TLR4:
TLR4 does not directly bind to LPS. Some important proteins to associate with TLR4/LPS in your brain are MD2, LPS-binding protein and CD14. MD2 binds to TLR4 and allows it to move to the cell surface. LPS-binding protein binds LPS in the bloodstream and transfers it to CD14 on phagocytes. CD14 then associates with TLR4, completing receptor activation.
The end result of TLR activation is production of interferons. The major players in this signalling pathway are NFκB, interferon regulatory factor (IRF) and mitogen-activated protein kinases (MAPKs). This signalling pathway is more completely described here.
Cytoplasmic Receptors
Cytoplasmic receptors are used in sensing intracellular pathogens, and produce a signal that alerts the adaptive immune system. The two major cytoplasmic receptors are the NOD-like receptors and the RIG-like receptors.
NOD-like Receptors
The NOD-like receptors (NLRs) activate similar NFκB pathways as TLRs, to induce the adaptive immune response. These receptors recognize primarily peptidoglycan. After recognizing this ligand, NOD recruits RIPK2, which activates NFκB downstream. NOD-like receptors are also involved in pyroptosis, a form of cell death associated with fever. More information on pyroptosis here.
RIG-like Receptors
RIG-like receptors bind to viral RNAs in the cell cytoplasm. Of these receptors, RIG-I is the most well known. After binding to viral RNA, RIG receptors activate a protein called MAVS. This protein activates other proteins which subsequently activate NFκB and IRF3 (part of TLR signalling) downstream.
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