AI Article Synopsis
- TLR4 signaling is essential for starting immune responses, typically studied with isolated cells and low concentrations of lipopolysaccharide (LPS).
- Researchers created models using human cells and mice to explore TLR4's role in natural tissue environments rich in endogenous substances.
- Findings show that the extracellular matrix inhibits TLR4 signaling, and when the matrix is broken down, it releases agonists that activate the receptor, suggesting that the release from inhibition is the key initial step for TLR4's immune response activation.
Article Abstract
Signaling through Toll-like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by sub-nanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor. We developed an in vitro model system using the human cell line HEK 293 and an in vivo model using mice that have normal or that lack TLR4 receptors to study how TLR4 functions in such microenvironments. Here we report that signaling through TLR4 is strongly inhibited by intact extracellular matrix and that inhibition is abrogated and endogenous agonist(s) are liberated when the matrix is degraded. Thus, release from inhibition rather than direct stimulation by agonists such as LPS is the critical first event by which TLR4 initiates immune responses.
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| http://dx.doi.org/10.1096/fj.04-3211fje | DOI Listing |
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