TLR4

TLR4 is a pattern-recognition receptor that detects bacterial lipopolysaccharide (LPS) and drives innate immune activation with pro-inflammatory cytokine and chemokine production^[1]. Mechanistically, TLR4-MD-2 recognizes LPS, and the solved TLR4-MD-2-LPS structure explains ligand recognition and receptor activation^[2]. After LPS engagement, TLR4 signals through TIRAP-MyD88 at the plasma membrane and then through TRAM-TRIF from early endosomes to induce interferon-β responses^[3]. Therefore, TLR4 trafficking links receptor localization to inflammatory signaling magnitude and duration^[4]. In disease models, abnormal TLR4 signaling associates with sepsis, endotoxemia, acute lung injury, rheumatoid arthritis, and cardiovascular diseases^[5]. Compared with related TLR isoforms, TLR4 is distinguished by LPS recognition through the MD-2 complex and sequential MyD88/TRIF signaling^[2][3]. For experimental applications, TLR4 inhibitors may downregulate TLR4, bind TLR4 or TLR4/MD-2, or bind MD-2 to suppress pathway activation^[5]. However, eritoran, an MD2-TLR4 antagonist, did not significantly reduce sepsis-induced mortality in a phase 3 trial^[6].