TLR4: A Drug Target / Biomarker (G7099)

NCBI ID: G7099

TLR4

TLR4: A Drug Target / Biomarker

TLR4, also known as Toll-like receptor 4, plays a significant role in various cellular processes, including immune responses and metabolic regulation. In Drosophila, Toll activation in fat body cells leads to the recruitment of Pelle kinase, resulting in the release of antimicrobial transcription factor Dif. Similarly, in human immune cells such as macrophages and dendritic cells, TLR4 activation stimulates inflammatory responses through NF-kappaB and IRF3 pathways, and can also regulate metabolic responses.

Furthermore, TLR4 is associated with the cystic fibrosis transmembrane conductance regulator (CFTR) in cholangiocytes, where it governs the secretion of bicarbonate into bile for proper bile flow and digestion. Absence of CFTR due to mutations disrupts biliary secretion and affects the bile acid receptor TGR5, leading to impaired bile properties and progression of liver diseases.

In macrophages, TLR4 signaling is regulated by low-avidity signaling of beta2-integrin, which inactivates MyD88 and TRIF. This occurs through phosphorylation of the beta2-integrin DAP12 adaptor ITAM, attracting SYK and leading to separation of the cytoplasmic domains of beta2-integrin. Additionally, TLR4 signaling can be inhibited by ITAM-associated low-avidity signaling in macrophages. This process involves Cbl-b-mediated degradation of MyD88 and TRIF, ultimately regulating TLR4 signaling.

Furthermore, TLR4 activation in monocytes and its subsequent effects on brain endothelial cells have been studied. In this context, TLR4 activation leads to changes in the cargo of monocyte-derived exosomes, specifically miRNAs, which are taken up by brain endothelial cells. This uptake results in abnormal upregulation of adhesion molecules, chemoattractants, and pro-inflammatory cytokines, mediated by the TLR4/NF-kappaB pathway.

In summary, TLR4 plays diverse roles in different cellular processes and organisms. Its activation leads to the recruitment of various kinases and transcription factors, regulating immune responses, metabolic activities, and bile secretion. Regulation of TLR4 signaling involves the interaction with CFTR, low-avidity signaling of beta2-integrin, and the cargo of monocyte-derived exosomes. Understanding these mechanisms is crucial for elucidating the role of TLR4 in immunity and disease .
Based on the provided context information, the key viewpoints regarding TLR4 are as follows:

TLR4 activation by SLO protein produced by GAS in patients with obstructive sleep apnea syndrome (OSAS) leads to the production of cysteinyl leukotrienes (CysLTs) and subsequent proliferation of tonsillar helper T cells and plasma B cells, resulting in irreversible tonsil hyperplasia.

Wnt2b negatively regulates TLR4 signaling, which has inhibitory effects on hematopoietic stem cell (HSC) activation and liver fibrosis.

HMGB1 can activate macrophages and monocytes through binding to TLR4, leading to the release of cytokines and inflammation. HMGB1 also interacts with RAGE to modulate endothelial and tumor cell function.

The recognition of CPMV (cowpea mosaic virus) by TLR2, TLR4, and TLR7 activates downstream signaling pathways mediated by MyD88, ultimately inducing antiviral responses and inflammatory cytokine production.

SREC-I, in cooperation with TLRs such as TLR2 and TLR4, plays a role in triggering immunity by recognizing molecules derived from pathogens and activating inflammatory cascades, as well as processing and presenting acquired antigens to T cells.

Overall, TLR4 is involved in various signaling pathways and interactions with other molecules, contributing to immune responses, inflammation, and the development of certain pathological conditions.

Protein Name: Toll Like Receptor 4

Functions: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195, PubMed:21393102). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759). Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465)

The "TLR4 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about TLR4 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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