Toll-like receptor 4 (TLR4): new insight immune and aging

Abstract

TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane’s surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.

S100a9 might act as a modulator of the Toll-like receptor 4 transduction pathway in chronic rhinosinusitis with nasal polyps

“…This amplification facilitates specific biochemical cascades that alter cellular functions. For instance, the activation of TLR4 by its ligands, such as LPS, triggers a cascade of intracellular signaling that leads to the transcriptional activation of genes involved in immune and inflammatory responses 66 . Some central intracellular signaling pathways positively regulated by TLR4 include the NF-κB 67 , MAPK 68 , IRF3 69 and PI3K-Akt 70 pathways.…”

Metadichol® induced expression of the TLR family of receptors in PBMCs

“…Additionally, TLR4 inhibition has been studied in the context of myocardial inflammation, cardiovascular disease, allergic diseases, obesity-associated metabolic diseases, and neuronal degeneration. TLR4 has also been reported to be associated with age-related diseases, further highlighting its potential significance in disease research (49). Furthermore, TLR4 inhibitors are being researched for their potential in the treatment of severe COVID-19 and related disorders (50.51).…”

Endotoxin tolerance and trained immunity: breaking down immunological memory barriers

“…Consecutive intraperitoneal injections of low-dose LPS for 4 days gave rise to systemic ET after the second LPS administration, while TI was induced at the same time point in the brain, indicating a tissue-specific pattern or dynamics ( 133 ). Therefore, different TLRs, despite sharing upstream signalling components such as MyD88 and TRIF ( 134 – 136 ), can generate either ET or TI, but the context must be considered to establish this balance as the generation of one or the other might depend on the cellular environment (lack of neutrophils), route of administration (mucosal) or tissue location (brain).…”

“…Focusing on TLR4 as master LPS receptor, the signalling pathways triggered following this recognition involve both MyD88 and TRIF, with the latter leading to type I interferon production ( 134 ). This rises to possibility that a differential or preferential activation of one or the other could conduct towards a trained or tolerant phenotype.…”