Category: immune_innate
Toll-like receptors (TLRs) are the founding family of pattern-recognition receptors — 10 functional in humans (TLR1-10), each recognizing pathogen- or damage-associated molecular patterns (PAMPs / DAMPs). Cell-surface TLRs (TLR1/2/4/5/6/10) sense bacterial cell-wall components: TLR2 dimerizes with TLR1 or TLR6 for triacyl- vs diacyl-lipopeptide discrimination; TLR4 senses LPS (via MD-2 + CD14); TLR5 senses flagellin. Endosomal TLRs (TLR3/7/8/9) sense nucleic acids: TLR3 dsRNA; TLR7/8 ssRNA (imiquimod, resiquimod, vesatolimod are TLR7/8 agonists); TLR9 unmethylated CpG-DNA. Two adapter pathways: (1) MyD88-dependent (all TLRs except TLR3) → IRAK4 → IRAK1/2 → TRAF6 → TAK1 → IKK + MAPK → NF-κB + AP-1 → pro-inflammatory cytokines (TNF-α, IL-6, IL-1β); (2) TRIF-dependent (TLR3 + TLR4) → TBK1 → IRF3 → type I IFN. TLR4 uses both. Output: rapid antimicrobial defense (acute), priming of adaptive immunity (DC maturation, antigen presentation). Clinical: TLR7/8 agonists are vaccine adjuvants (imiquimod for genital warts/BCC); TLR9 antagonists (hydroxychloroquine, chloroquine) for SLE/RA; TLR4 antagonist eritoran (failed sepsis trials); JAK inhibitors block downstream type-I IFN. Dysregulation: chronic TLR signaling underlies many autoimmune diseases + sepsis cytokine storm. Cross-links: [[cgas_sting_type1_ifn]] (parallel innate branch), [[nfkb_signaling]] (downstream), [[jak_stat_signaling]] (type I IFN output).