TLR2TLR4

TLR2TLR4 is not a distinct receptor but a shorthand used to describe the functional interaction or cross-talk between Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) signaling pathways in innate immunity. TLRs detect microbial motifs and initiate inflammatory responses. TLR4 recognizes lipopolysaccharide (LPS) from Gram-negative bacteria in complex with MD-2 and CD14; TLR2 forms heterodimers with TLR1 or TLR6 to recognize triacyl and diacyl lipopeptides, respectively. While TLR2 primarily signals through the adaptor MyD88, TLR4 signals via both MyD88 and the TRIF adaptor, yielding distinct but overlapping transcriptional programs including NF-κB, MAPKs, and IRF3/7 dependent responses.

Functional cross-talk has been observed when both receptors are engaged, leading to synergistic or amplified expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12, as well as chemokines. Cross-talk can occur at shared downstream signaling molecules, transcription factors, and regulatory feedback mechanisms (e.g., SOCS, IRAK-M), and may modulate the balance between inflammatory and tolerogenic responses. The exact nature of TLR2-TLR4 cross-talk can depend on cell type, ligand sets, and temporal patterns of signaling.

Physiological relevance includes host defense against bacterial infections and the pathogenesis of inflammatory diseases. Genetic variations or environmental factors altering TLR2 or TLR4 signaling can influence susceptibility and severity of sepsis, sepsis-associated organ injury, or autoimmune conditions. Therapeutic strategies sometimes target TLR2 or TLR4 signaling, or their downstream adapters, to modulate excessive inflammation.