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TLR9
TLR9 Full Name
toll-like receptor 9
TLR9 Introduction
TLR9 is a PRR family member and an important immune defense against invading pathogens. In contrast to most other TLRs, TLR9 is an endosomal receptor and is only expressed in a membrane-bound organelle of endoplasmic reticulum and endosomes. TLR9 is primarily involved in the recognition of PAMPs including unmethylated CpG dinucleotide motifs that are enriched in bacterial and viral DNA. TLR9 is quickly activated by binding to its cognate ligands such as CpG oligodeoxynucleotides and this triggers downstream signaling cascades which are typically MyD88 dependent and result in the activation of important transcription factors, such as NF-κB. This leads to the expression of a host of pro-inflammatory cytokines and chemokines to recruit and activate both innate and adaptive immune responses, resulting in clearance of invading pathogens. TLR9 is thus one of the first lines of the body's defense against external infections and its accurate recognition and activation is of great importance to immune homeostasis.
On the other hand, however, inappropriate TLR9 activation is also crucial in the pathogenesis of autoimmune diseases, such as SLE. For example, in the SLE patient, increased release of self-DNA fragments into circulation (secondary to defective apoptosis or clearance of apoptotic debris) may lead to formation of immune complexes with autoantibodies. Immune complexes may then be endocytosed by B cells or pDCs and activate TLR9 in the endosomes to recognize self-DNA. In this way, inappropriate self-recognition disrupts immune tolerance, and has pathogenic consequences: excessive TLR9 activation leads to overproduction of type I interferon (a key cytokine in SLE pathogenesis), and directly drives B cell activation, proliferation, and autoantibody production, including anti-dsDNA antibodies.
In spite of its role in autoimmunity, TLR9 has been highly promising in cancer immunotherapy. The basic therapeutic concept is to use TLR9 agonists to simulate the "danger signals" in pathogen infection and thereby "wake up" the body's own anti-tumor immune response. The effects of TLR9 agonists are achieved by multiple mechanisms: direct activation of dendritic cells and B cells in the tumor microenvironment, facilitation of antigen presentation, and induction of a strong Th1-type cellular immune response. This approach can be used as a single therapy or, more interestingly, has synergistic effects when used in combination with other therapies.
Figure 1. TLR9 role in different diseases. (Source: Saber MM, et al. 2022)
Alternate Names for TLR9
TLR9; toll-like receptor 9; CD289;
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