| First Author | Perkins DJ | Year | 2018 |
| Journal | Nat Immunol | Volume | 19 |
| Issue | 12 | Pages | 1309-1318 |
| PubMed ID | 30397349 | Mgi Jnum | J:282512 |
| Mgi Id | MGI:6381123 | Doi | 10.1038/s41590-018-0243-7 |
| Citation | Perkins DJ, et al. (2018) Autocrine-paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling. Nat Immunol 19(12):1309-1318 |
| abstractText | 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-beta 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. |
