Toll-like receptor signaling pathway

Toll-like receptors (TLRs) are essential cellular receptors that function as the first line of defense against microbes. They can identify invading pathogens and danger signals released by dying cells and damaged tissues, and are key in linking adaptive and innate immunity.  It is now recognized that innate immunity is given significant specificity by the diverse array of TLRs expressed in cells and tissues that can effectively distinguish between a large variety of distinct pathogens and the body's own cells¹.

Toll was initially discovered as a gene responsible for controlling the dorsal-ventral polarity of the Drosophila embryo, but it was later found to play a role in antifungal immunity. TLRs are type I transmembrane proteins characterized by 20 to 27 extracellular leucine-rich repeats (LRRs) that facilitate the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).  The extracellular domains contain glycan moieties which act as ligand binding sites for pathogen associated ligand; however, the specific mechanisms of glycan-mediated ligand recognition are not fully understood².

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To date, ten members of the human TLR family and 13 of the mouse TLR family have been identified, with TLR10 being non-functional in mice. TLR4, the first Toll protein homolog discovered in humans, induces the expression of inflammatory response genes in response to lipopolysaccharides (LPS), a family of molecules that coat a wide variety of bacteria. TLRs can be divided into those expressed at the cell membrane, which include TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10, and those expressed intracellularly, such as TLR3, TLR7, TLR8, and TLR9, with the endoplasmic reticulum, endosomes, and lysosomes.
 TLRs are expressed on all innate immune cells, including macrophages, natural killer cells, dendritic cells, and circulating leukocytes like monocytes and neutrophils. In addition, they are present in adaptive immune cells, such as T and B lymphocytes, and non-immune cells, including epithelial cells, endothelial cells, and fibroblasts. Most cells and tissues throughout the body will express some variety of TLRs in order to detect either pathogen, or tissue and genetic damage.

TLR signaling is complex, and in mammals, five different types of signaling adaptor proteins can be recruited by the TLR intracellular TIR domain. These are the Myeloid differentiation primary-response protein 88 (MyD88), TIR domain-containing adaptor protein (TIRAP or MAL), TIR domain-containing adaptor protein inducing IFN-β (TRIF), TRIF-related adaptor molecule (TRAM), and sterile α- and armadillo-motif-containing protein (SARM). The MyD88 signaling cascade is essential for TLRs 2, 4, 5, 7, 8, and 9. TIRAP is also activated in a MyD88-dependent manner and is associated with TLR2 and TLR4. In contrast, TRIF operates independently of MyD88, mediating signal transduction following TLR3 and TLR4 activation. TRAM facilitates TLR4 signaling in a MyD88-independent and TRIF-dependent manner. Moreover, SARM acts as a negative regulator of TRIF, thereby modulating signaling through TLR3 and TLR4³. The combination of TLRs and signaling adaptors allows the body to tailor the cellular and immune response to wide variety of triggering events.
Most TLR activation triggers either an inflammatory response, which acts as a defensive mechanism for the body, or a response that elicits regeneration and repair. When the regulatory mechanisms of TLR signaling fail, improper activation can disrupt tissue homeostasis, and lead to a feedback loop that enhances the secretion of inflammatory cytokines. In some cases these responses can contribute to inflammatoryand autoimmune disorders, such as respiratory and cardiovascular conditions, diabetes, digestive issues, and microbial infections. In addition, it may create an environment favorable for cancer development⁴.
Our poster outlines the key elements of the TLR signaling machinary and its contribution to innate immunity, the induction of adaptive immune responses, and its broader roles in health and disease.

References

1. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).

2. Duan, T., Du, Y., Xing, C., Wang, H. Y. & Wang, R. F. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity.  Front. Immunol.  13, 812774 (2022).

3. El-Zayat, S. R., Sibaii, H. & Mannaa, F. A. Toll-like receptors activation, signaling, and targeting: an overview.  Bull. Natl. Res. Cent.  43, 187 (2019).

4. Wang, K., Huang, H., Zhan, Q., Ding, H. & Li, Y. Toll-like receptors in health and disease.  Med. Comm.  5, e549 (2024).