Autocrine-paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling.
Darren J PerkinsKatharina RichardAnne-Marie HansenWendy LaiShreeram NallarBeverly KollerStefanie N VogelPublished in: Nature immunology (2018)
The unique cell biology of Toll-like receptor 4 (TLR4) allows it to initiate two signal-transduction cascades: a signal dependent on the adaptors TIRAP (Mal) and MyD88 that begins at the cell surface and regulates proinflammatory cytokines, and a signal dependent on the adaptors TRAM and TRIF that begins in the endosomes and drives the production of type I interferons. Negative feedback circuits to limit TLR4 signals from both locations are necessary to balance the inflammatory response. We describe a negative feedback loop driven by autocrine-paracrine prostaglandin E2 (PGE2) and the PGE2 receptor EP4 that restricted TRIF-dependent signals and the induction of interferon-β through the regulation of TLR4 trafficking. Inhibition of PGE2 production or antagonism of EP4 increased the rate at which TLR4 translocated to endosomes and amplified TRIF-dependent activation of the transcription factor IRF3 and caspase-8. This PGE2-driven mechanism restricted TLR4-TRIF signaling in vitro after infection of macrophages by the Gram-negative pathogens Escherichia coli or Citrobacter rodentium and protected mice against mortality induced by Salmonella enteritidis serovar Typhimurium. Thus, PGE2 restricted TLR4-TRIF signaling specifically in response to lipopolysaccharide.
Keyphrases
- toll like receptor
- inflammatory response
- nuclear factor
- gram negative
- escherichia coli
- immune response
- lps induced
- lipopolysaccharide induced
- transcription factor
- multidrug resistant
- type diabetes
- dendritic cells
- stem cells
- cell surface
- cardiovascular events
- listeria monocytogenes
- adipose tissue
- cardiovascular disease
- risk factors
- insulin resistance
- coronary artery disease
- antimicrobial resistance
- biofilm formation