A comparative review of toll-like receptor 4 expression and functionality in different animal species

Abstract

Toll-like receptors (TLRs) belong to the pattern recognition receptor (PRR) family, a key component of the innate immune system. TLRs detect invading pathogens and initiate an immediate immune response to them, followed by a long-lasting adaptive immune response. Activation of TLRs leads to the synthesis of pro-inflammatory cytokines and chemokines and the expression of co-stimulatory molecules. TLR4 specifically recognizes bacterial lipopolysaccharide, along with several other components of pathogens and endogenous molecules produced during abnormal situations, such as tissue damage. Evolution across species can lead to substantial diversity in the TLR4's affinity and specificity to its ligands, the TLR4 gene and cellular expression patterns and tissue distribution. Consequently, TLR4 functions vary across different species. In recent years, the use of synthetic TLR agonists as adjuvants has emerged as a realistic therapeutic goal, notably for the development of vaccines against poorly immunogenic targets. Given that an adjuvanted vaccine must be assessed in pre-clinical animal models before being tested in humans, the extent to which an animal model represents and predicts the human condition is of particular importance. This review focuses on the current knowledge on the critical points of divergence between human and the mammalian species commonly used in vaccine research and development (non-human primate, mouse, rat, rabbit, swine, and dog), in terms of molecular, cellular, and functional properties of TLR4.

Keywords: dog; human; mouse; non-human primate; rabbit; rat; swine; toll-like receptor 4.

Figure 1

LPS sensing via LBP and the CD14/MD-2/TLR4 receptor complex. TLR4 consists of an extracellular domain with leucine-rich repeats (LRR), a hypervariable domain (HYP), a transmembrane domain (TM), and a cytoplasmic domain with a highly conserved TIR-domain. After binding to LBP in serum, LPS is transferred to CD14 and then to the MD-2/TLR4 complex. This illustration is based on mouse and human TLR4 knowledge.

Figure 2

TLR4 intracellular signaling cascade. The MyD88-dependent pathway induces NF-κB translocation and expression of pro-inflammatory cytokine genes. The MyD88-independent pathway induces NF-κB or IRF3 translocation, leading to expression of pro-inflammatory cytokine genes by NF-κB or IFN-β and TNF-α genes by IRF3. This canonical signaling pathway is based on published mouse and human TLR4 knowledge.

Figure 3

Alignment of human TLR4 gene and protein. Exon 1 encodes a signal peptide and initial amino acids of the extracellular domain. Exon 2 encodes first LRRs in the extracellular domain. Exon 3 encodes the remaining extracellular domain (hypervariable region and LRRs), the transmembrane domain and the cytoplasmic domain. TM, transmembrane domain; HYP, hypervariable region.