Abstract
Toll-like-receptor (TLR) family members were detected in the central nervous system (CNS). TLR occurrence was noticed and widely described in glioblastomamultiforme (GBM) cells. After ligand attachment, TLR-4 reorients domains and dimerizes, activates an intracellular cascade, and promotes further cytoplasmatic signaling. There is evidence pointing at a strong relation between TLR-4 signaling and micro ribonucleic acid (miRNA) expression. The TLR-4/miRNA interplay changes typical signaling and encourages them to be a target for modern immunotherapy. TLR-4 agonists initiate signaling and promote programmed death ligand-1 (PD-1L) expression. Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression. Another potential target for immunotreatment is connected with limited TLR-4 signaling that promotes Wnt/DKK-3/claudine-5 signaling, resulting in a limitation of GBM invasiveness. Interestingly, TLR-4 expression results in bordering proliferative trends in cancer stem cells (CSC) and GBM. All of these potential targets could bring new hope for patients suffering from this incurable disease. Clinical trials concerning TLR-4 signaling inhibition/promotion in many cancers are recruiting patients. There is still a lot to do in the field of GBM immunotherapy.
Highlights
Various toll-like-receptor (TLR) family members are detected in the central nervous system (CNS)
toll-like receptors (TLRs)-4 is detected in two main types of cells: microglial and macroglial cells
Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression controlled by the PD-1L/PD-1 axis [125,126,127]
Summary
Various toll-like-receptor (TLR) family members are detected in the central nervous system (CNS). Many autoregulating mechanisms control inflammation that is mediated through TLR signaling Their activity concerns the nucleus level (countering the expression of cytokines and interleukins (TTP, ATF3, and REG-1) and the cytoplasmatic level (STAT1, AhR, Nurr1); the inhibition of adaptor complex suppressor of cytokine signaling, sterile alpha-and armadillo-motif-containing protein (SOCS1, SARM); and the cell-surface level interrupting dimerization processes: suppressor of tumorigenicity 2, single immunoglobulin IL-1R-related molecule, Rickettsia prowazekii 105 (ST2, SIGGR, and RP105) [29,30,31,32,33]. TLR-4, after particular antigen attachment to a pathogen-associated molecular patterns (PAMP) or DAMP, is shifted from the cell surface to form the endosome during phagocytosis (Table 2).
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