Autocrine prostaglandin feedback governs the kinetics of bacterial induced type I interferon by driving autophagic targeting of the TLR4/TRIF complex

Abstract TLR4 is unique in its capacity to initiate two qualitatively distinct transcriptional programs from two cellular locations. Cell surface TLR4/MyD88 complexes drive pro-inflammatory cytokine transcription through NF-kB, while endosomal TLR4/TRIF complexes activate IRF3 and a type I interferon response. Feedback circuits to limit signals from both locations are necessary to balance the inflammatory response to Gram negative bacteria, yet how endosomal TLR4/TRIF signals are terminated remains an open question. It has been reported previously that engagement of TLR4 triggers activation of autophagic machinery and that macrophages defective in core autophagy genes display selective hyper activation of the TRIF versus MyD88 pathways in response to LPS. Previous studies from our lab have shown that TLR4 activation induces rapid synthesis and secretion of the immunomodulatory host lipid Prostaglandin E2 (PGE2) which selectively diminishes endosomal TLR4/TRIF signaling. In this ongoing study we find that, mechanistically, autocrine PGE2 signals downstream of TLR4 significantly enhance activation of autophagic processes to likely negatively regulate the persistence of endosomal TLR4/TRIF complexes and define the kinetics of TRIF signaling through directed autophagy. Supported by a grant from the NIH R21AI151352