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).
Organ Systems
immune-hematologic
integumentary
respiratory
Pathway Steps
PAMP / DAMP (LPS, dsRNA, CpG, flagellin, etc.) → TLR ligand binding + receptor dimerization — via TLR2 with TLR1/6 partner; others homodimerize; CD14 + MD-2 cofactors for TLR4-LPS. TLRs are the prototypical pattern-recognition receptors, each detecting a conserved microbial molecule (LPS, dsRNA, CpG DNA, flagellin) or host danger signal. Ligand binding dimerizes the receptor; surface TLRs sense membrane PAMPs while endosomal TLRs (3/7/8/9) sense nucleic acids — the basis of self/non-self discrimination.
TLR-TIR domain → MyD88 (all but TLR3) recruitment — via IRAK4 → IRAK1/2 → TRAF6 → TAK1 → IKK + MAPK. Dimerization juxtaposes the cytoplasmic TIR domains, creating a platform that recruits adaptor proteins. All TLRs except TLR3 signal through MyD88, which assembles the “Myddosome” with IRAK kinases — the trunk of the pathway leading to NF-κB and MAPK activation.
TRIF (TLR3 + TLR4) → TBK1 → IRF3 phosphorylation — via endosomal pathway → type I IFN (IFN-α/β) → ISG induction. TLR3 (and TLR4 from the endosome) instead use the adaptor TRIF, which activates TBK1 to phosphorylate IRF3, driving type-I interferon. This MyD88-independent branch is how TLRs mount antiviral interferon responses — the same IRF3/IFN output used by the cytosolic nucleic-acid sensors.
TAK1 → IKKβ → IκB phosphorylation → degradation — via NF-κB nuclear translocation → TNF/IL-6/IL-1β transcription. Downstream of MyD88, the kinase TAK1 activates the IKK complex: IKKβ phosphorylates IκB, marking it for degradation and freeing NF-κB to enter the nucleus. This is the convergence point shared with TNF and IL-1 signaling — the central inflammatory transcription switch.
TAK1 → p38 + JNK → AP-1 — via parallel pro-inflammatory transcription. TAK1 also activates the MAP kinases p38 and JNK, which drive the AP-1 transcription factor. The MAPK/AP-1 arm cooperates with NF-κB to shape the inflammatory gene program and links innate sensing to cell-stress and proliferation responses.
NF-κB + AP-1 + IRF3 → cytokine + chemokine release — via DC maturation, neutrophil recruitment, T-cell priming → adaptive bridge. The combined activation of NF-κB, AP-1, and IRF3 transcribes pro-inflammatory cytokines (TNF, IL-6, IL-1β), chemokines, and interferons — the innate output that triggers inflammation and instructs adaptive immunity. Excess or chronic TLR signaling underlies sepsis and inflammatory/autoimmune disease.
Known Modulators
hydroxychloroquine (inhibitor) — TLR7/9 (lysosomal acidification block). SLE + RA core; mechanism via endosomal TLR inhibition