TLR Signalling Pathways Diverge in Their Ability to Induce PGE₂

Abstract

PGE2 is a lipid mediator abundantly produced in inflamed tissues that exerts relevant immunoregulatory functions. Dendritic cells (DCs) are key players in the onset and shaping of the inflammatory and immune responses and, as such, are well known PGE2 targets. By contrast, the precise role of human DCs in the production of PGE2 is poorly characterized. Here, we asked whether different ligands of Toll-like receptors (TLRs), a relevant family of pathogen-sensing receptors, could induce PGE2 in human DCs. The only active ligands were LPS (TLR4 ligand) and R848 (TLR7-8 ligand) although all TLRs, but TLR9, were expressed and functional. While investigating the molecular mechanisms hindering the release of PGE2, our experiments highlighted so far oversight differences in TLR signalling pathways in terms of MAPK and NF-κB activation. In addition, we identified that the PGE2-limiting checkpoint downstream TLR3, TLR5, and TLR7 was a defect in COX2 induction, while TLR1/2 and TLR2/6 failed to mobilize arachidonic acid, the substrate for the COX2 enzyme. Finally, we demonstrated the in vivo expression of PGE2 by myeloid CD11c+ cells, documenting a role for DCs in the production of PGE2 in human inflamed tissues.

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

“…Using TLR4 triggering as a model for MSK1-driven cDC2 activation, pSS cDC2s produced higher levels of IL-12 and TNF-α, suggesting that the increased expression of MSK1 contributes to their enhanced cytokine production. In addition, MSK1 activation is downstream of several TLRs (31, 40), in-line with the downregulation of miR-130a upon TLR triggering. Thus, pSS cDC2s have decreased expression of miR-130a and increased expression of MSK1, associated with increased production of TNF-α and IL-12.…”

Adaptive Regulation of Osteopontin Production by Dendritic Cells Through the Bidirectional Interaction With Mesenchymal Stromal Cells

“…PGE 2 released by MSCs was identified as the main soluble factor responsible for this inhibition. This conclusion is supported by multiple experimental approaches, including the use of IDM to block PGE 2 production, the pharmacological blocking of the two main PGE 2 receptors expressed by DCs, namely EP2 and EP4, and the increasing of intracellular concentration of cyclic AMP, the main second messenger downstream EP2/EP4 activation ( 53 – 55 ).…”

Podosomes, But Not the Maturation Status, Determine the Protease-Dependent 3D Migration in Human Dendritic Cells

“…Using PGE 2 , which is synthesized downstream of LPS stimulation and mediates podosome dissolution ( 44 , 46 ), we showed that it maintained DC in an immature state and abolished migration in Matrigel concomitantly to podosome disruption. In contrast to the TLR4 signaling pathway, PGE 2 is not produced upon TLR2 stimulation ( 47 ), and thus podosomes are maintained. Due to the unique ability of DC to dissolve their podosomes, this study further supports the critical role of these cell structures in 3D migration in dense environments.…”