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Toll-like receptors: Roles in disease and therapy

Authors
Douglas McDonald, MD, PhD
Francisco A Bonilla, MD, PhD
Section Editor
Jordan S Orange, MD, PhD
Deputy Editor
Anna M Feldweg, MD

INTRODUCTION

Toll-like receptors (TLRs) are cell surface and intracellular molecules on eukaryotic cells that detect and respond to microbial antigens. They derive their name from homology to the Drosophila Toll molecule, an important component of dorsal-ventral patterning and antifungal defense [1,2]. TLRs are part of the innate immune system, which is a phylogenetically ancient system present in invertebrates and conserved through vertebrate evolution. Innate immune responses are initiated rapidly by exposure to microbes and precede the development of adaptive immune responses [3]. Innate immunity is reviewed separately. (See "An overview of the innate immune system" and "Immunity of the newborn".)

ROLE IN INNATE IMMUNITY

TLRs are a type of pattern recognition receptor (PRR), which are receptors specific for molecular components of micro-organisms that are not made by the host. The ligands for TLRs are called pathogen-associated molecular patterns (PAMPs), which are components of pathogenic microbes. In vertebrates, TLRs initiate protective functions that operate independently from adaptive immunity. They also play a critical role in adaptive immune responses by directing the differentiation of naïve T cells into effector T cells. Other examples of PRRs include nucleotide oligomerization domain (NOD)-like receptors (NLRs) and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). (See "An overview of the innate immune system", section on 'Pattern recognition receptors'.)

STRUCTURE AND FUNCTION OF TLRs

Different species have different numbers of distinct TLRs. At least 10 have been discovered in humans [1,2,4]. With the exception of TLR1, TLR2, and TLR6, TLRs initiate signaling by homodimerization (eg, two identical TLRs brought together). TLR2 forms heterodimers with TLR1 (TLR2/1) or TLR6 (TLR2/6). Receptor structure/organization, ligands, and signaling are summarized in the table (table 1) and figure (figure 1).

The structure of all of the TLRs is similar. All have an extracellular ligand recognition and binding domain that contains leucine-rich repeats. All have a single transmembrane domain. The cytoplasmic (signaling) domain is homologous to the interleukin-1 (IL-1) receptor and is called a toll/IL-1 receptor or TIR domain.

The final common pathway for TLR signaling involves the transcription factors, nuclear factor (NF) for the kappa light chain enhancer in B cells (NF-kappa-B) and activating protein-1 (AP-1). These transcription factors regulate a multitude of genes, including those encoding important proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), IL-1-beta, IL-6, IL-8, and IL-12. Some TLRs also activate production of type 1 (alpha and beta) interferons by inducing the interferon regulatory factors (IRFs) IRF3, IRF5, and IRF7.

                               

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Literature review current through: Jul 2017. | This topic last updated: Apr 24, 2017.
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