Toll-like receptors (TLRs)

Toll-like receptors (TLRs) are ten surface and endosomal pattern recognition receptors forming a primary sensing layer of innate immunity. Cell-surface TLRs (TLR1, TLR2, TLR4, TLR5) detect bacterial lipoproteins, lipopolysaccharide, and flagellin; endosomal TLRs (TLR3, TLR7, TLR8, TLR9) recognise microbial nucleic acids. Each carries a leucine-rich repeat ectodomain and a cytoplasmic TIR domain recruiting MyD88 or TRIF, activating NF-κB, IRF3/7, and MAP kinases to drive TNF-α, IL-1β, IL-6, and type I interferons. Beyond PAMPs, TLRs respond to damage-associated molecular patterns (DAMPs) — HMGB1, oxidised lipids, heat-shock proteins, mislocated self-DNA — released by stressed or dying cells. This sterile DAMP-driven activation is central to inflammaging: the chronic low-grade inflammation linked to cardiovascular disease, neurodegeneration, and increased all-cause mortality in older adults. TLR2 directly governs the senescence-associated secretory phenotype (SASP); Hari et al. (2019, Science Advances) showed TLR2 is markedly induced during oncogene-driven senescence, and its knockdown strongly reduced IL-1β, IL-6, IL-8, and CCL20, affecting over 1,000 downstream genes. TLR4 expression rises in aged innate immune cells; extracellular HSP70/HSP90 acts as an endogenous TLR4 agonist, sustaining NF-κB independently of infection. A miR-146a feedback loop normally restrains TLR/NF-κB output; Olivieri et al. (2013) showed its dysregulation in aged macrophages removes this brake. Human intervention trial evidence is absent as of 2026.