Pattern-recognition receptors

Innate cells cannot generate new receptors, so they rely on a limited set of inherited receptors tuned to molecules that are essential to microbes and absent from healthy host cells — pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycan and lipoteichoic acid, flagellin, unmethylated CpG DNA, double-stranded viral RNA and fungal β-glucans and mannans. The same receptors respond to damage-associated molecular patterns (DAMPs) released by stressed or necrotic cells — ATP, uric-acid and cholesterol crystals, HMGB1, heat-shock proteins and mitochondrial DNA — explaining sterile inflammation.

Toll-like receptors (TLRs), ten in humans, sit on the cell surface (TLR1/2/6 — bacterial lipoproteins and lipoteichoic acid; TLR4 — Gram-negative LPS, with MD-2 and CD14; TLR5 — flagellin) or in endosomes, where they detect nucleic acids (TLR3 — dsRNA; TLR7/8 — ssRNA; TLR9 — CpG DNA). They signal through the adaptors MyD88 and/or TRIF to activate NF-κB (pro-inflammatory cytokines, co-stimulatory molecules) and interferon-regulatory factors (type I interferons). Cytosolic sensors include NOD1/NOD2 (peptidoglycan fragments), NLRP3 and other NLRs that assemble the inflammasome — activating caspase-1 to process pro-IL-1β and pro-IL-18 and trigger pyroptotic cell death — RIG-I/MDA5 (viral RNA) and cGAS–STING (cytosolic DNA). C-type lectin receptors (mannose receptor, dectin-1, DC-SIGN) and soluble PRRs (mannose-binding lectin, CRP, ficolins) complete the system.

PRR signalling in dendritic cells induces co-stimulatory molecules and cytokines, which is how innate recognition "licenses" adaptive immunity — and why vaccine adjuvants are often PRR agonists.