Autocrine–paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling

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 E 2 (PGE 2 ) and the PGE 2 receptor EP4 that restricted TRIF-dependent signals and the induction of interferon-β through the regulation of TLR4 trafficking. Inhibition of PGE 2 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 PGE 2 -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, PGE 2 restricted TLR4–TRIF signaling specifically in response to lipopolysaccharide. Endosomal TLR4 signaling activates type I interferons via a TRIF-dependent pathway. Vogel and colleagues identify autocrine production of PGE 2 –EP4–cAMP as a negative regulator of the TRIF pathway that suppresses IFN-β expression induced by Gram-negative bacteria.