{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTLR4 is a central sensor of microbial lipopolysaccharide (LPS) and related ligands, whose engagement with its coreceptor MD‐2 triggers receptor dimerization, the recruitment of adaptor proteins (including MyD88, TRAM, and TICAM‐1/2), and the initiation of canonical proinflammatory signaling cascades. Structural and biochemical studies have revealed that diverse LPS molecules are accommodated within a hydrophobic pocket of MD‐2, leading to receptor multimerization and downstream activation events – such as the generation of reactive oxygen species via a direct interaction with NAD(P)H oxidase 4 – which are essential for host defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTLR4-driven inflammatory responses contribute to a wide array of systemic pathologies. Engagement of TLR4 on cells such as platelets can trigger the formation of neutrophil extracellular traps during severe sepsis, while its activation by altered self molecules like oxidized low‐density lipoprotein and myeloid proteins (e.g. Mrp8) amplifies inflammatory circuits in atherosclerosis, liver injury, and rheumatoid arthritis. Moreover, inappropriate TLR4 signaling has been linked to impaired barrier function in the intestine and kidney damage in diabetic nephropathy, as well as to inflammation associated with obesity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIntracellular regulation of TLR4 signaling is achieved both by dynamic receptor trafficking and by inhibitory feedback mechanisms. Endocytic recycling controls the cell‐surface availability of TLR4, while negative regulators such as RP105 and post‐transcriptional mechanisms governed by microRNAs (for example, members of the let‐7 family and exosome‐delivered miR-181c) fine tune the magnitude and duration of the inflammatory response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond recognition of LPS, TLR4 binds to a broad spectrum of endogenous and environmental ligands – including heat shock proteins, HMGB1, components from Porphyromonas gingivalis, histones, and even cereal‐derived inhibitors – often in cooperation with TLR2. This versatility enables TLR4 to mediate microglial activation in neurodegenerative disorders and to participate in diverse danger‐signal responses that extend the realm of innate immunity beyond classical bacterial infections."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various tissues, tight regulation of TLR4 expression is required to balance protective immunity with the prevention of chronic inflammation. In epithelial organs such as the intestine, lung, and biliary tract, TLR4 expression is maintained at low levels and is further modulated by cytokines and extracellular matrix components like hyaluronan fragments. Similarly, mesenchymal stem cells employ TLR4 signaling to influence T-cell responses, highlighting the receptor’s role in tissue-specific immune modulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variations and aberrant regulation within the TLR4 signaling network can alter disease susceptibility and progression, including in oncogenic processes. 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