Autocrine-Paracrine Prostaglandin E(2) 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 Mal (TIRAP)–MyD88-dependent signal from the cell surface that regulates proinflammatory cytokines and a TRAM–TRIF-dependent signal from endosomes that drives type I interferon production. 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, which restricted TRIF-dependent signals and IFN-β induction through regulation of TLR4 trafficking. Inhibition of PGE(2) production or EP4 antagonism increased the rate of TLR4 endosomal translocation, and amplified TRIF-dependent IRF3 and caspase 8 activation. This PGE(2)-driven mechanism restricted TLR4-TRIF signaling in vitro upon infection of macrophages by Gram-negative pathogens Escherichia coli and Citrobacter rodentium and protected mice against Salmonella enteritidis serovar Typhimurium (ST)-induced mortality. Thus, PGE(2) restricts TLR4-TRIF signaling specifically in response to lipopolysaccharide.