The PTGS2/COX2-PGE₂ signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus

Abstract

Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E 2 (PGE 2 ), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE 2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2 -PGE 2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE 2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.

LRH-1/NR5A2 Activation Rewires Immunometabolism Blunting Inflammatory Immune Cell Progression in Individuals with Type 1 Diabetes and Enhances Human Islet Function in Mice

“…This is evidenced by the activation of key molecular pathways inducing tolerance, such as OXPHOS, PPAR signalling, lysosome, and phagosome, as well as a specific subset of tolerogenic-associated genes, including PTGS2. Previously, we demonstrated that PTGS2 and its product, prostaglandin E 2, endow a tolerogenic phenotype to DCs after efferocytosis and prevent cytokine-induced apoptosis in BL001-treated islet β-cell 22,23,82 . Consistent with a shift towards a tolerogenic phenotype, levels of several cell surface markers associated with mDCs (CXCR4 and CD54) were decreased, as did the secretion of IL-7 in cells treated with BL001.…”

“…Nonetheless, these approaches have yet to reach ethical approval for clinical trials. Pharmacological activation of LRH-1/NR5A2 could circumvent these caveats encountered by cell therapy by attenuating the pro-inflammatory environment-without suppressing the general immune system-while increasing β-cell survival and performance 22,23 .…”

“…BL001 coordinated in vivo the resolution, rather than the suppression, of the autoimmune attack, by increasing the number of anti-inflammatory M2 while decreasing the number of pro-inflammatory M1 macrophages, and concomitantly increasing the number of IDO + tolerogenic dendritic cells and Tregs. In parallel, BL001 stimulated β-cell regeneration via trans-differentiation and improved cell survival, the latter involving the PTGS2/PGE 2 /PTGER1 signalling cascade 21–23 .…”

“…In parallel, BL001 stimulated b-cell regeneration via trans-differentiation and improved cell survival, the latter involving the PTGS2/PGE2/PTGER1 signalling cascade [21][22][23] .…”

“…Our previous work provided an early proof-of-concept that pharmacological activation of LRH-1/NR5A2 using a small chemical agonist (BL001) could therapeutically impede the progression of hyperglycemia in 2 mouse models (NOD and RIP-B7.1) of experimental autoimmune diabetes (EAD), validating the benefits of targeting this NR 20 . BL001 coordinated the resolution, rather than the suppression, of the auto-immune attack, concomitantly with the stimulation of β-cell regeneration via trans-differentiation as well as improved cell survival, the latter involving the PTGS2/PGE2/PTGER1 signalling cascade 20-22 .…”