Pattern recognition receptors in health and diseases

Abstract

Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

Fig. 1

The signal transduction pathways and structure of TLR-binding ligand complex. TLRs can recognize one or more PAMPs through LRR domain. They usually dimerize themselves and recruit adaptor molecules with the same TIR domain to transmit signals

Fig. 2

Crystal structure of TLRs with ligands. a Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide (PDB 2Z7X). TLR2 initiates immune responses by recognizing di-acylated and tri-acylated lipopeptides. The ligand specificity of TLR2 is controlled by whether it heterodimerizes with TLR1 or TLR6. Binding of the tri-acylated lipopeptide (red) induced the formation of M-type crystal structures of the TLR1 (pale yellow) and TLR2 (slate) ectodomains. b Crystal structure of TLR2–TLR6–Pam2CSK4 complex (PDB 3A79). Binding of the di-acylated lipopeptide, Pam2CSK4 (red), induced the formation of M-type crystal structures of the TLR2 (slate) and TLR6 (pale green) ectodomains. c Crystal structure of mouse TLR4/MD2/LPS complex (PDB 3VQ2). After LPS (red) binds with the TLR4 (yellow)/MD2 (gray) complex, the hydrophobic pocket of MD2 is used to bridge the two TLR4–MD2–LPS complexes to form a spatially symmetrical M-type structure. Mouse TLR4/MD2/LPS exhibited an complex similar to the human TLR4/MD2/LPS complex. d Crystal structure of the N-terminal fragment of zebrafish TLR5 in complex with Salmonella flagellin (PDB 3V47). Two TLR5 (cyan)–flagellin (firebrick) 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex to function

Fig. 3

The ligand recognition mechanism of NLRs. The combination of PAMP and LRR changes the conformation of NLRs from self-inhibition to activation

Fig. 4

Structural features and ligand recognition mechanism of RLRs. The structure and functions of MDA5 are similar to those of RIG-I. However, MDA5 lacks the repressor domain, so it does not have self-inhibitory functions. LGP2 does not have CARD, and so it cannot transmit signals. The combination of viral RNA and CTD changes the conformation of RLRs

Fig. 5

Pattern recognition receptor-mediated NF-κB signaling. The NF-κB protein can regulate gene expression and affect various biological processes, including innate and adaptive immunity, inflammation, stress response, B cell development, and lymphoid organ formation. TLRs, NLRs, RLRs, and CLRs can generally phosphorylate IκB protein, which inhibits the activation of NF-κB protein, thereby promoting the transcription and activation of inflammatory genes

Fig. 6

Pattern recognition receptor-mediated TBK1-IRF-3 signaling. Intracellular induction of pathogens is carried out through the detection of foreign molecular components (including cytoplasmic viral and bacterial nucleic acids). Once detected, the innate immune system induces type I interferon (IFN) production through the TANK-binding kinase 1 (TBK1)-interferon regulatory factor-3/7 (IRF-3/7) pathway. IRF-3/7 can be activated through two innate immune antiviral signal pathways, TLR3/TLR4-TIR domain-containing adaptor protein-inducing interferon β (TRIF) and RIG-I-MAVS, and then dimerize and merge into the nucleus to work

Fig. 7

Pattern recognition receptor-mediated inflammasome signaling. One way for pathogenic microorganisms to induce inflammation is by activating inflammasomes, which are multi-protein complexes assembled by PRRs in the cytoplasm and activate caspase-1 and subsequent activation of pro-inflammatory cytokines IL-1β and IL-18. The inflammasome complex usually contains cytoplasmic PRRs, adaptor protein (ASC), and pro-caspase-1. Many different inflammasome complexes have been detected, each with unique PRRs and activation triggers