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INNATE IMMUNITY 3
PATTERN RECOGNITION
RECEPTORS
The innate immune system is an evolutionally conserved mechanism that provides an early and effective response
against invading microbial pathogens. It relies on a limited set of pattern recognition receptors (PRRs) that
recognize specific pathogen-associated molecular patterns (PAMPs) commonly present in microbes but not in
host. Upon detection of PAMPs, the PRRs trigger an inflammatory response that recruits phagocytic cells, induce
antimicrobial peptides and cytokine/chemokine secretion, leading to efficient destruction of the invading
pathogens. Three main families of PRRs have been shown to initiate proinflammatory signaling pathways: the
Toll-Like receptors (TLRs), the NOD-Like receptors (NLRs) and RIG-I-Like receptors (RLRs).
Toll-Like Receptors (TLRs)
TLRs are the first identified and best characterized receptors among the signaling PRRs. They initiate key inflammatory responses and also shape adaptative
immunity. All TLRs (10 in humans and 11 in mice) are type I transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic
tail that contains a conserved region called the Toll/IL-1 receptor (TIR) domain. They recognize a variety of PAMPs from bacteria, fungi, parasites, and viruses,
including lipid-based bacterial cell wall components such as lipopolysaccharide (LPS) and lipopeptides, microbial protein components such as flagellin, and
nucleic acids such as single-stranded or double-stranded RNA and CpG DNA. TLRs initiate shared and distinct signaling pathways by recruiting different
combinations of four TIR-domain-containing adaptor molecules: MyD88, TIRAP (MAL), TRIF (TICAM1) and TRAM (TICAM2). These signaling pathways
activate the transcription factors NF-kB and AP-1 leading to the production of inflammatory cytokines and chemokines. They also activate interferon
regulatory factors (IRFs) leading to the production of type I interferons.
Nod-Like Receptors (NLRs)
NOD-Like Receptors (NLRs, also known as CATERPILLERs) constitute a recently identified family of intracellular pattern recognition receptors (PRRs),
which contains more than 20 members in mammals. Although the ligands and functions of many of these receptors are not known, their primary role is to
recognize cytoplasmic pathogen-associated molecular patterns (PAMPs) and/or endogenous danger signal, inducing immune responses. NLRs are
characterized by a tripartite-domain organization with a conserved nucleotide binding oligomerization domain (NOD) and leucine-rich repeats (LRRs). The
general domain structure consists of C-terminal LRRs involved in microbial sensing, a centrally located NOD domain and an N-terminal effector region
comprising a protein-protein interaction domain such as the CARD, Pyrin or BIR domain. NLRs have been grouped into several subfamilies on the basis of
their effector domains: NODs, NALPs, CIITA, IPAF, and NAIPs. NODs and IPAF contain CARD effector domains, whereas NALPs and NAIPs contain pyrin
(PYD) effector domains and three BIR domains, respectively.
RIG-I-Like Receptors (RLRs)
RIG-I-like receptors (RLRs) constitute a family of cytoplasmic RNA helicases that are critical for host antiviral responses. RIG-I (retinoic-acid-inducible
protein 1, also known as Ddx58) and MDA-5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) sense double-stranded RNA
(dsRNA), a replication intermediate for RNA viruses, leading to production of type I interferons (IFNs) in infected cells. A third RLR has been described:
laboratory of genetics and physiology 2 (LGP2). LGP2 contains a RNA binding domain but lacks the CARD domains and thus acts as a negative feedback
regulator of RIG-I and MDA-5.
C-Type Lectin Receptors (CLRs) and Other Pathogen Sensors
Besides TLRs, NLRs and RLRs, other receptors can also recognize molecules present on pathogenic organisms. Those receptors include members of the
PGRP (peptidoglycan recognition proteins) and C-type lectin families. C-type lectins, also called C-type lectin receptors (CLRs), encompass a large family of
proteins that act as phagocytic receptors that bind carbohydrate moieties of various pathogens. This family comprises MBL (mannose binding lectin),
Dectin-1, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin) and the structurally related receptors SIGNRs.
48 www.invivogen.com/innate-immunity