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

• Published in: Journal of cellular physiology 2021-02, Vol.236 (2), p.877-888
• Main Authors: Bruning, Elise E., Coller, Janet K., Wardill, Hannah R., Bowen, Joanne M.
• Format: Article
• Language: English
• Subjects: Adaptive systems; Dendritic cells; Disease; Epithelial cells; Epithelium; Gastrointestinal system; Gastrointestinal tract; Homeostasis; Immune system; immunity; Immunoglobulin A; Immunological memory; inflammation; Inflammatory diseases; Innate immunity; Intestine; intestines; Microbiomes; mucous membrane; Permeability; Priming; Receptors; TLR4 protein; Toll-like receptors; Toll‐like receptor 4
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29976

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. Toll‐like receptor 4 (TLR4) is a highly conserved protein of innate immunity, expressed on a variety of cell types including epithelial and immune cells. In a healthy condition, there is a clear distinction in the site‐specific roles of TLR4 in epithelial cells versus immune cells for maintaining homeostasis. Recent research has indicated the importance of site‐specific TLR4 expression in inflammation and disease; 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.