This review paper covers what is known of toll-like receptors in the development of age-related chronic inflammation, with a particular focus on toll-like receptor 4 (TLR4). A sizable number of researchers are focused on finding ways to suppress the constant overactivation of the immune system in later life by interfering in its regulation. Unfortunately, the sensing mechanisms involved are also required for normal immune function, so it is hard to envisage even sophisticated implementations of this strategy producing therapies that don’t inhibit necessary immune functions, such as defense against pathogens and destruction of potentially cancerous cells. The better approach is to repair the underlying molecular damage and disarray that triggers toll-like sensors, such as the mitochondrial dysfunction that allows mislocalization of mitochondrial DNA into the cytoplasm where it is mistaken for bacterial DNA. This is not a sizable focus in the research and development community, alas.
Toll-like receptor (TLR) is a type of pattern recognition receptor (PRR) that plays a crucial role in the immune system. PRRs, predominantly expressed by innate immune cells such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells, serve as sentinels of the body’s defenses. They become activated upon detecting pathogen-associated molecular patterns (PAMPs), which are molecular signatures unique to external pathogens and distinct from host components, as well as damage-associated molecular patterns (DAMPs), encompassing molecules like heat shock proteins (HSPs) and plasma membrane components released due to cellular damage or death. PRR is a major factor in innate immunity and also plays a role initiating adaptive immunity through induce the maturation of dendritic cells and the release of inflammatory cytokines.
TLR activation serves as a defense mechanism for the host against infections and tissue damage, initiating a signaling cascade that leads to the secretion of various inflammatory cytokines and the activation of immune cells. Notably, TLR4, a pivotal member of the innate immune response, becomes activated by diverse ligands classified as PAMPs and DAMPs. However, excessive TLR4 activation disrupts immune homeostasis by sustaining pro-inflammatory cytokine and chemokine production, thus contributing to the onset and progression of various diseases, including Alzheimer’s disease, cancer, osteoarthritis, and sepsis.
The aging process significantly impacts the immune system, fostering a bidirectional influence termed ‘immunosenescence’. Cellular senescence triggers the release of senescence-associated secretory phenotype (SASP), which can induce inflammation, subsequently promoting the generation of damage-associated molecular patterns (DAMPs), and escalating the exposure and circulation of externally infiltrated pathogen-associated molecular patterns (PAMPs) due to barrier deterioration. Diverse factors heightened by the aging process result in aberrant immune system regulation through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), consequently affecting cardiovascular, metabolic, and age-related degenerative diseases. In this review, we delineate the role of TLR4, a pivotal component of the immune system, and its association with aging-related diseases, thereby shedding light on the significance of TLR4 signaling in disease research.
Link: https://doi.org/10.1186/s12979-023-00383-3
