Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines. PRRs are regulated through a variety of pathways ensure optimal immune and inflammatory response to invaders.
The microbe-specific molecules that are recognized by a given PRR are called pathogen-associated molecular patterns (PAMPs) and include bacterial carbohydrates (such as lipopolysaccharide or LPS, mannose), nucleic acids (such as bacterial or viral DNA or RNA), bacterial peptides (flagellin, microtubule elongation factors), peptidoglycans and lipoteichoic acids (from Gram-positive bacteria), N-formylmethionine, lipoproteins and fungal glucans and chitin. PRRs exhibit significant diversity in coevolution with PAMPs. Endogenous stress signals are called damage-associated molecular patterns (DAMPs) and include uric acid and extracellular ATP, among many other compounds. There are several subgroups of PRRs. They are classified according to their ligand specificity, function, localization and/or evolutionary relationships.
Types and signaling Based on their localization, PRRs may be divided into membrane-bound PRRs and cytoplasmic PRRs: Membrane-bound PRRs include toll-like receptors (TLRs) and C-type lectin receptors (CLRs). Cytoplasmic PRRs include NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs).
PRRs were first discovered in plants. Since that time many plant PRRs have been predicted by genomic analysis (370 in rice; 47 in Arabidopsis). Unlike animal PRRs, which are associated with intracellular kinases via adaptor proteins (see non-RD kinases below), plant PRRs are composed of an extracellular domain, transmembrane domain, juxtamembrane domain and intracellular kinase domain as part of a single protein.
Toll-like receptors (TLR) Recognition of extracellular or endosomal pathogen-associated molecular patterns is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them their specific appearance and are also responsible for TLR functionality. Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. 10 functional members of the TLR family have been described in humans so far. Studies have been conducted on TLR11 as well, and it has been shown that it recognizes flagellin and profilin-like proteins in mice. Nonetheless, TLR11 is only a pseudogene in humans without direct function or functional protein expression. Each of the TLR has been shown to interact with a specific PAMP.
TLR signaling TLRs tend to dimerize, TLR4 forms homodimers, and TLR6 can dimerize with either TLR1 or TLR2. Interaction of TLRs with their specific PAMP is mediated through either MyD88-dependent pathway and triggers the signaling through NF-κB and the MAP kinase pathway and therefore the secretion of pro-inflammatory cytokines and co-stimulatory molecules or TRIF – dependent signaling pathway. MyD88 – dependent pathway is induced by various PAMPs stimulating the TLRs on macrophages and dendritic cells. MyD88 attracts the IRAK4 molecule, IRAK4 recruits IRAK1 and IRAK2 to form a signaling complex. The signaling complex reacts with TRAF6 which leads to TAK1 activation and consequently the induction of inflammatory cytokines. The TRIF-dependent pathway is induced by macrophages and DCs after TLR3 and TLR4 stimulation. Molecules released following TLR activation signal to other cells of the immune system making TLRs key elements of innate immunity and adaptive immunity.
C-type lectin receptors (CLR) Many different cells of the innate immune system express a myriad of CLRs which shape innate immunity by virtue of their pattern recognition ability. Even though, most classes of human pathogens are covered by CLRs, CLRs are a major receptor for recognition of fungi: nonetheless, other PAMPs have been identified in studies as targets of CLRs as well e.g. mannose is the recognition motif for many viruses, fungi and mycobacteria; similarly fucose presents the same for certain bacteria and helminths; and glucans are present on mycobacteria and fungi. In addition, many of acquired nonself surfaces e.g. carcinoembryonic/oncofetal type neoantigens carrying "internal danger source"/"self turned nonself" type pathogen pattern are also identified and destroyed (e.g. by complement fixation or other cytotoxic attacks) or sequestered (phagocytosed or ensheathed) by the immune system by virtue of the CLRs. The name lectin is a bit misleading because the family includes proteins with at least one C-type lectin domain (CTLD) which is a specific type of carbohydrate recognition domain. CTLD is a ligand binding motif found in more than 1000 known proteins (more than 100 in humans) and the ligands are often not sugars. If and when the ligand is sugar they need Ca2+ – hence the name "C-type", but many of them do not even have a known sugar ligand thus despite carrying a lectin type fold structure, some of them are technically not "lectin" in function.
CLR signaling There are several types of signaling involved in CLRs induced immune response, major connection has been identified between TLR and CLR signaling, therefore we differentiate between TLR-dependent and TLR-independent signaling. DC-SIGN leading to RAF1-MEK-ERK cascade, BDCA2 signaling via ITAM and signaling through ITIM belong among the TLR-dependent signaling. TLR-independent signaling such as Dectin 1, and Dectin 2 – mincle signaling lead to MAP kinase and NFkB activation.
Membrane receptor CLRs have been divided into 17 groups based on structure and phylogenetic origin. Generally there is a large group, which recognizes and binds carbohydrates, so called carbohydrate recognition domains (CRDs) and the previously mentioned CTLDs.
Another potential characterization of the CLRs can be into mannose receptors and asialoglycoprotein receptors.
Group I CLRs: The mannose receptors The mannose receptor (MR) is a PRR primarily present on the surface of macrophages and dendritic cells. It belongs into the calcium-dependent multiple CRD group. The MR belongs to the multilectin receptor protein group and, like the TLRs, provides a link between innate and adaptive immunity. It recognizes and binds to repeated mannose units on the surfaces of infectious agents and its activation triggers endocytosis and phagocytosis of the microbe via the complement system. Specifically, mannose binding triggers recruitment of MBL-associated serine proteases (MASPs). The serine proteases activate themselves in a cascade, amplifying the immune response: MBL interacts with C4, binding the C4b subunit and releasing C4a into the bloodstream; similarly, binding of C2 causes release of C2b. Together, MBL, C4b and C2a are known as the C3 convertase. C3 is cleaved into its a and b subunits, and C3b binds the convertase. These together are called the C5 convertase. Similarly again, C5b is bound and C5a is released. C5b recruits C6, C7, C8 and multiple C9s. C5, C6, C7, C8 and C9 form the membrane attack complex (MAC).
Group II CLRs: asialoglycoprotein receptor family This is another large superfamily of CLRs that includes the classic asialoglycoprotein receptor macrophage galactose-type lectin (MGL), DC-SIGN (CLEC4L), Langerin (CLEC4K), Myeloid DAP12‑associating lectin (MDL)‑1 (CLEC5A), DC‑associated C‑type lectin 1 (Dectin1) subfamily, and DC immunoreceptor (DCIR) subfamily. Furthermore, Dectin subfamily and DCIR subfamily consist of some members as follow. DC‑associated C‑type lectin 1 (Dectin1) subfamily includes dectin 1/CLEC7A, DNGR1/CLEC9A, Myeloid C‑type lectin‑like receptor (MICL) (CLEC12A), CLEC2 (also called CLEC1B)- the platelet activation receptor for podoplanin on lymphatic endothelial cells and invading front of some carcinomas, and CLEC12B; while DC immunoreceptor (DCIR) subfamily includes DCIR/CLEC4A, Dectin 2/CLEC6A, Blood DC antigen 2 (BDCA2) ( CLEC4C), and Mincle i.e. macrophage‑inducible C‑type lectin (CLEC4E).
The nomenclature (mannose versus asialoglycoprotein) is a bit misleading as these the asialoglycoprotein receptors are not necessarily galactose (one of the commonest outer residues of asialo-glycoprotein) specific receptors and even many of this family members can also bind to mannose after which the other group is named.
NOD-like receptors (NLR)
The NOD-like receptors (NLRs) are cytoplasmic proteins, which recognize bacterial peptidoglycans and mount proinflammatory and antimicrobial immune response. Approximately 20 of these proteins have been found in the mammalian genome and include nucleotide-binding oligomerization domain (NODs), which binds nucleoside triphosphate. Among other proteins the most important are: the MHC Class II transactivator (CIITA), IPAF, BIRC1 etc.
The ligands are currently known for NOD1 and NOD2. NOD1 recognizes a molecule called meso-DAP, which is a peptidoglycan constituent only of Gram negative bacteria. NOD2 proteins recognize intracellular MDP (muramyl dipeptide), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. When inactive, NODs are in the cytosol in a monomeric state and they undergo conformational change only after ligand recognition, which leads to their activation. NODs transduce signals in the pathway of NF-κB and MAP kinases via the serine-threonine kinase called RIP2. NODs signal via N-terminal CARD domains to activate downstream gene induction events, and interact with microbial molecules by means of a C-terminal leucine-rich repeat (LRR) region.
The interaction and cooperation among different types of receptors typical for the innate immune system has been established. An interesting cooperation has been discovered between TLRs and NLRs, particularly between TLR4 and NOD1 in response to Escherichia coli infection. Another proof of the cooperation and integration of the entire immune system has been shown in vivo, when TLR signaling was inhibited or disabled, NOD receptors took over role of TLRs.