Toll‐like receptors in pathogenesis of neurodegenerative diseases and their therapeutic potential

Abstract

Toll‐like receptors (TLRs) are a family of pattern‐recognition receptors triggered by pathogen‐derived and tissue‐damage‐related ligands. TLRs were previously believed to only be expressed in immune cells. However, it is now confirmed that they are ubiquitously expressed in cells within the body including neurons, astrocytes, and microglia of the central nervous system (CNS). Activation of TLRs is capable of inducing immunologic and inflammatory responses to injury or infection of CNS. This response is self‐limiting that usually resolves once the infection has been eradicated or the tissue damage has been repaired. However, the persistence of inflammation‐inducing insults or a failure in normal resolution mechanisms may result in overwhelming inflammation which may induce neurodegeneration. This implies that TLRs may play a role in mediating the link between inflammation and neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. So, new therapeutic approaches that specifically target TLRs may be developed by better understanding TLR expression mechanisms in the CNS and their connections to particular neurodegenerative disorders. Therefore, this review paper discussed the role of TLRs in neurodegenerative diseases.

Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation

“…Pathogen recognition receptors, including TLR4, which mediates inflammatory responses by recognizing lipopolysaccharide (LPS) and TLR2 (Lehnardt et al, 2002 ; Hwang et al, 2016 ), could be directly involved in this amplified response since their expression is increased in the mutant cell lines, in basal condition for Tlr4 , and upon LPS stimulation for Tlr2 . Of note, other TLR encoding genes figured among the DEGs both in basal conditions (induction of Tlr1, Tlr3 , and Tlr13 in the mutant cells) and after LPS treatment (induction of Tlr3 and Tlr12 and repression of Tlr5 and Tlr8 ), suggesting that peroxisome defect impacts not only neuroinflammation but also adaptive immunity and antiviral response (Kumar, 2019 ; Dabi et al, 2023 ).…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…TLR2 is a prominent member among TLRs within the CNS. An examination of its immunoreactivity in the neurogenic regions of the adult brain has uncovered its presence on cells in both the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles associated with neurogenesis ( 225 ).…”

Ethanol Induces Neuroinflammation in a Chronic Plus Binge Mouse Model of Alcohol Use Disorder via TLR4 and MyD88-Dependent Signaling

“…However, chronic neuroinflammation is believed to contribute to neuropathology in a variety of disorders, including AUD [ 14 , 15 , 16 , 17 ]. Toll-like receptors (TLRs) are a family of evolutionarily conserved proteins that play critical roles in immune responses as well as responses to cell damage [ 18 ]. They are type I transmembrane proteins whose extracellular domains bind to pattern-associated molecular patterns (PAMPs) found on pathogens, and damage-associated molecular pathogens (DAMPs) produced by cell damage.…”

“…TRAF activation also results in the activation of MAP kinases and the production of Fos and Jun, which dimerize to form the transcription factor AP1. These transcription factors activate the transcription of genes encoding a variety of pro-inflammatory cytokines, chemokines, COX2, and iNOS [ 18 , 28 , 29 ]. The MYD88-independent (TRIF-dependent) pathway involves TLR4 interaction with TRIF, which then recruits the TRIF-related adaptor molecule (TRAM), allowing for the activation of the transcription factor interferon regulator factor 3 (IRF3).…”

“…The MYD88-independent (TRIF-dependent) pathway involves TLR4 interaction with TRIF, which then recruits the TRIF-related adaptor molecule (TRAM), allowing for the activation of the transcription factor interferon regulator factor 3 (IRF3). The transcription factor NF-ĸB is also activated in the TRIF-dependent pathway, but the kinetics of activation are slower than that observed in the MyD88-dependent pathway [ 18 , 28 ]. IRF3, the related IRF7 and NF-κB activate the transcription of genes that encode Type I Interferons such as IFN-β.…”