Site-specific contribution of Toll-like receptor 4 to intestinal homeostasis and inflammatory disease

Toll-like receptor 4 (TLR4) is a highly conserved protein of innate immunity, responsible for the regulation and maintenance of homeostasis, as well as immune recognition of external and internal ligands. TLR4 is expressed on a variety of cell types throughout the gastrointestinal tract, including on epithelial and immune cell populations. In a healthy state, epithelial cell expression of TLR4 greatly assists in homeostasis by shaping the host microbiome, promoting immunoglobulin A production, and regulating follicle-associated epithelium permeability. In contrast, immune cell expression of TLR4 in healthy states is primarily centred on the maturation of dendritic cells in response to stimuli, as well as adequately priming the adaptive immune system to fight infection and promote immune memory. Hence, in a healthy state, there is a clear distinction in the site-specific roles of TLR4 expression. Similarly, recent research has indicated the importance of site-specific TLR4 expression in inflammation and disease, particularly the impact of epithelial-specific TLR4 on disease progression. However, the majority of evidence still remains ambiguous for cell-specific observations, with many studies failing to provide the distinction of epithelial versus immune cell expression of TLR4, preventing specific mechanistic insight and greatly impacting the translation of results. The following review provides a critical overview of the current understanding of site-specific TLR4 activity and its contribution to intestinal/immune homeostasis and inflammatory diseases.

Automated summary

TLR4 is a highly conserved protein involved in innate immunity with distinct roles in epithelial and immune cells throughout the gastrointestinal tract. While epithelial cell expression of TLR4 contributes to maintaining homeostasis, promoting immunoglobulin A production, and regulating permeability, immune cell expression is centered on maturation of dendritic cells and priming the adaptive immune system. However, further research is needed to fully understand the impact of site-specific TLR4 expression on inflammation and disease progression.