Taking its TOLL: The role of Toll-like receptor 4 in human health and disease, and its potential as a therapeutic target

Phoebe Crammond^1*Priyanka Hastak¹Anthony Delaney^2,3Sarah C. Sasson^1*

• ¹Immunovirology and Pathogenesis Program, The Kirby Institute, Faculty of Medicine, University of New South Wales, Kensington, Australia
• ²Intensive Care Unit, Royal North Shore Hospital, St Leonards, Australia
• ³Critical Care Program, The George Institute for Global Health, Sydney, Australia

Toll-like receptor 4 (TLR4) is a pattern recognition receptor that binds to pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Binding of exogenous or endogenous ligands activates the TLR4 pathway and induces the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β and type 1 interferons including IFN-α and IFN-β. TLR4 plays a vital role in host defense against Gram-negative bacterial infections by recognizing lipopolysaccharides (LPS) and inducing inflammatory mediators to clear infection. However, there is emerging evidence that excessive TLR4 activation may be pathogenic in human diseases affecting the central nervous system, cardiovascular, respiratory and metabolic systems, thereby promoting inflammation and autoimmunity. In some diseases, the is conflicting evidence regarding pathogenic versus protective roles. Several TLR4 targeted therapeutics have been developed and studied in animal models, however many of these therapeutics including Eritoran and TAK-242 did not prove to be effective in clinical trials. Overall, TLR4 exhibits context-dependent protective and pathogenic roles across infectious and non-infectious diseases, reflecting the complexity of its signaling in human health and disease.