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Review
. 2024 Apr 29;5(5):e549.
doi: 10.1002/mco2.549. eCollection 2024 May.

Toll-like receptors in health and disease

Kunyu Wang  1 , Hanyao Huang  2 , Qi Zhan  1 , Haoran Ding  1 , Yi Li  1
Affiliations
Review

Toll-like receptors in health and disease

Kunyu Wang et al. MedComm (2020). .

Abstract

Toll-like receptors (TLRs) are inflammatory triggers and belong to a family of pattern recognition receptors (PRRs) that are central to the regulation of host protective adaptive immune responses. Activation of TLRs in innate immune myeloid cells directs lymphocytes to produce the most appropriate effector responses to eliminate infection and maintain homeostasis of the body's internal environment. Inappropriate TLR stimulation can lead to the development of general autoimmune diseases as well as chronic and acute inflammation, and even cancer. Therefore, TLRs are expected to be targets for therapeutic treatment of inflammation-related diseases, autoimmune diseases, microbial infections, and human cancers. This review summarizes the recent discoveries in the molecular and structural biology of TLRs. The role of different TLR signaling pathways in inflammatory diseases, autoimmune diseases such as diabetes, cardiovascular diseases, respiratory diseases, digestive diseases, and even cancers (oral, gastric, breast, colorectal) is highlighted and summarizes new drugs and related clinical treatments in clinical trials, providing an overview of the potential and prospects of TLRs for the treatment of TLR-related diseases.

Keywords: cancer; clinical treatment; disease; innate immunity; toll‐like receptors.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Cell surface TLRs and associated ligands. TLR1,TLR2, TLR4, TLR5, and TLR6 are mainly located on the cell surface. TLR2 usually forms a heterodimer with TLR1 or TLR6 and is involved in the recognition of a variety of PAMPs derived from bacteria, fungi, parasites, and viruses, such as lipopeptides from bacteria. In addition to primarily recognizing LPS on the cell surface, TLR4 can be internalized and retained in the endosome. TLR5 detects flagellin (a component of bacterial flagella).
FIGURE 2
FIGURE 2
Intracellular TLRs and related ligands. At steady state, TLR3, TLR7, TLR8, and TLR9 are primarily localized to the endoplasmic reticulum and transported to endolysosomes, where they bind their ligands. TLR3 recognizes dsRNA from viruses or damaged cells. TLR7 recognizes ssRNA from ssRNA viruses or damaged cells, and TLR9 recognizes DNA from DNA viruses and bacteria or damaged cells.
FIGURE 3
FIGURE 3
TLR signaling pathways. TLRs signaling can be divided into MyD88‐dependent and MyD88‐independent (TRIF‐dependent) signaling pathways. TLRs are located at the plasma membrane or endosomal membrane and are activated by binding to their ligands, leading to receptor dimerization and recruitment of adaptor proteins such as MyD88, TIRAP, TRIF, and TRAM. IRAK and TRAF6 stimulate TAK1 to activate the IKKγ complex, which further releases NF‐κB into the nucleus. Activated TAK1 also promotes MAPK activation, which in turn stimulates nuclear translocation of AP‐1. Both pathways support proinflammatory cytokine transcription. The MyD88‐independent pathway is activated by TLR3 and TLR4. The TIR domain of TLR recruits TRIF to form complexes containing TRAF3, TBK1, and IKK, which promote nuclear translocation of IRF3 or initiate late NF‐κB through interaction with RIP1 and subsequent TRAF6 activation. Both signal transduction stimulates type I interferon production.
FIGURE 4
FIGURE 4
Interactions of TLRs with inflammation and tumor. TLRs are expressed on a variety of cells, including tumor cells and immune cells. TLRs signaling is involved in the carcinogenesis of the tumor microenvironment. TLRs expressed on immune cells and tumor cells are subjected to activation by pamps, damps from microorganisms, viruses, parasites, injured and necrotic cancer cells.The release of cytokines and chemokines by these activated cells is an important part of the tumor microenvironment. Moreover, cytokine‐activated infiltrating immune cells can subsequently induce additional cytokines that impair the function of APCs, leading to tumor immune tolerance.
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