Toll-like receptors (TLRs) are a class of transmembrane proteins that play essential roles in mammalian innate immune responses against infection. In general, TLRs can recognize structurally conserved molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs), which derive from invading bacteria or viruses. Recognition of PAMPs by TLR-expressing cells result in acute responses necessary to clear the pathogens in the host. TLRs contain an intracellular toll/interleukin-1 (IL-1) receptor-like (TIR) domain that is critical for signal transduction, in addition to an extracellular leucine-rich repeat (LRR) domain.
TLRs are well conserved in both humans and mice, consisting of at least 11 members. TLR signaling in immune response has been extensively investigated using animal models in the last few decades. It has been known that TLRs are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. Accumulating evidence also reveals that TLRs may play a role in metabolic disorders or even malignancies. For example, Myd88, a major adapter protein for TLRs, plays an important role in RAS-MAPK signaling, cell-cycle control, and cell transformation. Additionally, the NF-κB signaling pathway, downstream of Myd88, is likely a link between chronic inflammation and tumor development.
As mice remain the foundation of in vivo immunological studies, it is important to consider the genetic differences brought about by over 65 million years of independent evolution since the species diverged from humans. Appropriate understanding of such species-specific differences will help researchers address the potential limitations of extrapolating data from mice to humans. While the overall structure of the immune system in humans and mice are very similar, there are often variations based on cell distribution, protein expression, and other phenotypic traits that are reflective of our divergent evolution. For example, human blood is neutrophil rich, while mouse blood predominately consists of lymphocytes. Humans also require a more extensive collection of B and T cells to be maintained for many years, up to fifty mouse lifetimes1.
Past research on Multiple Sclerosis (MS) provides a clear example of both the similarities and disparities between human and mouse immunology. Experimental autoimmune encephalomyelitis is widely used to model MS, as it simulates the demyelination of central and peripheral nerves caused be the disease. Mouse studies previously indicated IFN-γ as a protective agent, yet clinical trials had to be stopped because treatment with IFN-γ exacerbated the disease. On the contrary, mouse studies found that blocking VLA-4 (α4β1 integrin)-VCAM-1 interactions could mitigate MS – which ultimately has led to successful human trials and the subsequent FDA approval of the disease-modifying therapy known as natalizumab.
Recent research has shown that TLR4 genes are highly conserved across mammalian species; this is especially true for the intracellular TIR-domain – suggesting a similar signal transduction pathway2. There have been considerable differences found within TLR4 extracellular domains, which is likely due to the species-specific adaptations to address the rapidly changing microbial environment and reflects the need to bind to different ligands.
Herein, we uncover some of the similarities and differences in the TLR4 gene, amino acid sequences, expression patterns, and functionality of TLR4 across human and murine species. The mouse TLR4 gene is comprised of three exons, each of which correspond to a homologous sequence in the human gene. Murine and human TLR4 sequences share high similarities across the nucleotidic and amino acid levels, but the TLR4 locus exhibits slight genetic variations across mouse strains. The highest expression levels of TLR4 occur in cells of myeloid origin across both humans and mice, and TLR4 is also expressed by lymphoid cell types. Differential expression is found between the murine and human CNS: mice only express TLR4 in the microglia, it is not expressed in astrocytes nor oligodendrocytes. The shared functionality of TLR4 across human and mouse models is broad, as TLR4 is not only linked to the NF-κB signaling pathway, but may also be involved in cardiovascular diseases for both. The roles of TLRs are now being revisited by using more complicated mouse models, including conditional KO, marker tagged KI and conditional point mutation models.
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