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.

Human Coagulation Factor X-Adenovirus Type 5 Complexes Poorly Stimulate an Innate Immune Response in Human Mononuclear Phagocytes

“…MD-2 acts as a coreceptor for recognition of both exogenous ligands (43,44) and endogenous ligands (45,46). In addition, TLR4 can bind bacterial and viral PAMPs and, under inflammatory conditions, also endogenous damage-associated molecular pattern molecules (9). Importantly, the amino acid variability in the extracellular TLR4 ligand recognition domain changes the affinity for different agonists.…”

“…Importantly, the amino acid variability in the extracellular TLR4 ligand recognition domain changes the affinity for different agonists. The extracellular domains of mouse and human TLR4 show only 62% sequence similarity, while the hypervariable ligand binding regions have only 48% sequence similarity (9,47). Moreover, species differences for MD-2, the coreceptor for TLR4, also affect the ligand recognition (48,49) and the structural basis for these species differences has been resolved (50), which highlights the differences in PAMP recognition between mouse TLR4 and human TLR4 (51)(52)(53)(54).…”

“…Although there are differences that affect the transcriptional response and functionality of several leukocyte lineages (7,8) and TLR4 signaling (9), there are many features conserved between human and murine immune systems. Yet a recent pair of studies described contrasting interpretations-using the same data set-of the fidelity of mouse models with respect to mimicking human inflammatory diseases (59,60).…”

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

“…These effects were abrogated in the presence of PAFR antagonists or anti-CD36 blocking antibody [17]. Comparing to macrophages, DCs express less CD36 [32,33] and TLR4 in the membrane [34], thus these mechanisms above mentioned for macrophages are less significant in DCs. Additionally, it was demonstrated that PAFR activation induced CD36 expression in macrophages by mechanisms dependent on PPARγ [17].…”

Alteration of early dendritic cell activation by cancer cell lines predispose immunosuppression, which cannot be reversed by TLR4 stimulation

“…However, one major difference between human and mice DCs is the differential expression of TLRs. For example, human DCs only express low levels of TLR4 when compared with their mouse counterparts [42,43]. While lower TLR4 expression corresponds to a weaker response to LPS [44], a higher dose of LPS can still initiate DC activation [45].…”