Autocrine–paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling. (December 2018)

• Record Type: Journal Article
• Authors: Perkins, Darren; Richard, Katharina; Hansen, Anne-Marie; Lai, Wendy; Nallar, Shreeram; Koller, Beverly; Vogel, Stefanie
• Is Part Of: Nature immunology. Volume 19:Number 12(2018)
• Page Start: 1309
• Page End: 1318
• Publication Date: 2018-12
• Subjects: Immunology -- Periodicals; 571.9605
• DOI: 10.1038/s41590-018-0243-7
• Languages: English
• ISSNs: 1529-2908

Abstract

Abstract 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 pathogensEscherichia coli orCitrobacter rodentium and protected mice against mortality induced bySalmonella enteritidis serovar Typhimurium. Thus, PGE2 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 PGE2 –EP4–cAMP as a negative regulator of the TRIF pathway that suppresses IFN-β expression induced by Gram-negative bacteria.