Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer

Abstract

Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research.

FIG. 1.

Toll-like receptors (TLRs) and their ligands. TLRs share a common structural organization and consist of an ectodomain with multiple leucine-rich repeats (LRRs) involved in sensing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), a transmembrane region, and an intracellular tail with the TIR signaling domain. TLRs sense their agonists when expressed on the cell surface (e.g., TLR1, TLR2, TLR4, TLR5, and TLR6), and intracellular TLRs localized to the endosomal compartment detect microbial nucleic acids (see text for the detailed description).

FIG. 2.

Two TLR signaling pathways. LPS binds to coreceptors CD14 and MD2 that present it to TLR4, causing homodimerization and assembly of TIR domain-containing docking platforms that interact with sorting and signaling adapter proteins. TLR signals via Mal-MyD88 from the cell surface, leading to recruitment and activation of IRAK kinases and engagement of downstream adapters, kinases, and induction of proinflammatory cytokines and chemokines. After translocation to the endosomal compartment, TLR4 associates with TRAM and TRIF, engages TRAF-3, and activates TBK-1 and IKK-ɛ kinases, leading to phosphorylation, activation, and translocation of IRF3. By engaging RIP-1 and TRAF6, this pathway also leads to delayed activation of MAPKs and NF-κB. NF-κB and IRF-3 bind to consensus elements within the interferon (IFN)-β promoter, leading to expression of type I IFN and type I IFN-dependent genes.