TLR2, also known as Toll-like receptor 2 (TLR2), also known as CD282, is a pattern recognition receptor (PRR). TLR2 plays a crucial role in recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). It serves as a bridge between innate and adaptive immune responses. It serves as the first line of defense for detecting invading pathogens. TLR2 plays a crucial role in the pathogenesis of various autoimmune diseases and is the focus of much research and potential drug development for the treatment of infectious and inflammatory diseases, as well as for modulating allergic responses.

TLR2 expression

TLR2 is expressed in monocytes, macrophages, dendritic cells, neutrophils, endothelial cells, epithelial cells, and Langerhans cells, and is involved in cellular inflammatory responses and immune regulation.

(Data source: uniprot)

Structure of TLR2

TLR2 is a transmembrane protein composed of three structurally important components: a leucine-rich repeat motif at the N-terminus that recognizes ligands and facilitates PAMP recognition; a single transmembrane helix; and a conserved cytoplasmic Toll/interleukin-1 (IL-1) receptor (TIR) domain at the C-terminus that facilitates intracellular signal transduction. TLR2 can form homodimers with TLR1 and TLR6, respectively, to recognize different PAMPs. The TLR1/TLR2 dimer primarily recognizes triacyl lipopeptides from bacteria, while the TLR2/TLR6 dimer complex primarily recognizes diacyl lipopeptides, zymosan, and lipoteichoic acid.

(Data source: Gao W, et al. Front Physiol. 2017)

TLR2 signaling pathway and regulation:

TLR2 recognizes and binds to its specific ligands, such as bacterial lipoproteins and peptidoglycans. These ligands are typically recognized by TLR1 or TLR6, which form heterodimers with TLR2. Upon TLR2 activation, its intracellular TIR domain recruits the MyD88 adaptor protein. MyD88, an adaptor molecule containing a TIR domain, transmits TLR2 signals to downstream signaling molecules. The MyD88 pathway ultimately activates transcription factors including NF-κB and AP-1, promoting the expression of inflammatory cytokines and the inflammatory response.

(Data source: Duan T, et al. Front Immunol. 2022)

TLR2-targeted therapeutic strategies

TLR2 often plays a dual role during infection. On the one hand, TLR2 activation can generate a beneficial pro-inflammatory response that is crucial for controlling infection and promoting bacterial clearance. However, on the other hand, excessive TLR2 signaling can lead to tissue damage and disease progression by generating disproportionate inflammation.

Therapeutic inhibition of TLR2: TLR2-targeted inhibitors could limit the production of excessive, tissue-damaging proinflammatory cytokines or evasion of the host immune system. Tools with therapeutic potential for TLR2 inhibition include anti-TLR2 antibodies, small molecule inhibitors, synthetic inhibitory peptides, and TLR2 inhibitors produced by other pathogens.

Therapeutic Activation of TLR2: Activation of TLR2 signaling can help generate beneficial host immune responses generated by a variety of cell types.

TLR2 agonists: TLR2 agonists have emerged as potential targets for vaccine adjuvants and tumor immunity because they bind to TLR2 and activate APCs, enhancing their ability to uptake and process antigens and subsequently facilitating the activation of cytotoxic T lymphocytes and B cells to combat "threats" and tumor cells. TLR2 agonists serve as effective vaccine adjuvants because they are able to induce many different T cell responses, such as TH1, TH2, and TH17. This property facilitates the customization of vaccines to elicit specific immune responses. The inclusion of TLR2-derived adjuvants capable of generating specific T cell responses to relevant vaccine antigens will facilitate the design of more effective and targeted vaccines.

(Data source: Simpson ME, et al. Trends Mol Med. 2020)

NM-101 is a monoclonal antibody targeting TLR2 developed by Neuramedy . It blocks TLR2 to prevent the interneuronal spread of α-synuclein and neuroinflammation. It is currently in Phase 1 clinical trials for the treatment of Parkinson's disease (PD). Neuramedy has also developed a TLR2-targeting antibody, NM-103, for the treatment of other neurological diseases, which is currently in preclinical research.

(Data source: Neuramedy 's official website)

(Data source: New Drug Intelligence Database)