toll-like receptor 4 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding to toll-like receptor 4. [GOC:add, PMID:16551253, PMID:17328678]

Toll-like receptor 4 (TLR4) signaling is a critical pathway in the innate immune system, recognizing and responding to a wide array of microbial components, particularly lipopolysaccharide (LPS), a major component of Gram-negative bacterial outer membranes. This pathway triggers an intricate cascade of molecular events leading to the production of inflammatory cytokines and the activation of immune cells, ultimately orchestrating an effective defense against invading pathogens.

The signaling process begins with the recognition of LPS by TLR4, which is typically localized on the cell surface of immune cells like macrophages and dendritic cells. LPS binding to TLR4 initiates a series of conformational changes, leading to the recruitment of adaptor proteins, primarily MyD88 and TRIF.

The MyD88-dependent pathway, triggered by TLR4 activation, involves the recruitment and activation of IL-1R-associated kinases (IRAKs) and the downstream signaling molecule TNF receptor-associated factor 6 (TRAF6). TRAF6 activates the transcription factor NF-κB, leading to the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines mediate inflammation and contribute to the elimination of pathogens.

The TRIF-dependent pathway is activated by TLR4 in response to certain stimuli, like viral components or certain types of LPS. It involves the recruitment of TRIF, which activates the kinases TBK1 and IKKε, leading to the phosphorylation and activation of interferon regulatory factor 3 (IRF3). Activated IRF3 translocates to the nucleus and triggers the production of type I interferons (IFN-α and IFN-β), which possess antiviral and immunomodulatory properties.

The TLR4 signaling pathway can be further modulated by various mechanisms. Negative regulators, such as A20 and SOCS1, dampen the signaling cascade to prevent excessive inflammation. Additionally, crosstalk with other signaling pathways can influence the outcome of TLR4 activation.

In conclusion, TLR4 signaling represents a vital defense mechanism against microbial threats. Its intricate molecular network ensures the rapid and effective activation of immune cells, leading to the production of inflammatory mediators and the initiation of an immune response tailored to the specific pathogen. This pathway plays a crucial role in maintaining host homeostasis and protecting against infections.'
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Proteins (13)

Compounds (377)