Figure 4. Redox imbalance causes ferroptotic stress which can culminate in ferroptotic death in PMN-MDCSs.
The initiation of the ferroptotic program in redox-imbalanced cells results in the accumulation of polyunsaturated fatty acids- phospholipid (PUFA-PL) peroxidation products. FATP2 transports exogenous arachidonic acid from the TME to PMN-MDCS, and together with ACSL4 and FATP2, contributes to synthesis of PUFA-PL and the production of immunosuppressive signals in PMN-MDSC. Oxidized products specific for ferroptosis can be eliminated via an enzymatic action of either iPLA2β that hydrolyzes sn-2 hydroperoxyl (HOO)-PUFA-residue from hydroperoxy-PE species or by the reduction of HOO-PUFA-PE by GPX4. AA and its COX-catalyzed metabolite, PGE2, are mainly responsible for the immunosuppression. PGE2 can be presented in two forms – as a free oxygenated AA and also as PGE2-esterified into PE. PLA2-catalyzed hydrolysis of PGE2-PE may be required to release immunosuppressive free PGE2. Oxidized and oxidatively-truncated triacylglycerols are produced by PMN-MDSC in a MPO-catalyzed reaction and can be taken-up by dendritic cells. Accumulated oxidatively truncated forms of triacylglycerols prevent trafficking of pMHC from the phagosome/lysosome to the cell surface. These DCs are not able to effectively stimulate antigen-specific T cells due to suppressed antigen cross-presentation. Abbreviations: PMN-MDSC = polymorphonucler myeloid-derived suppressor cells; DC = dendritic cell; FATP2 = fatty acid transport protein 2; ACSL4 = Long chain acyl-CoA synthetase isoform 4; ALOX = arachidonate 15-lipoxygenase; GPX4 = Glutathione Peroxidase 4; GSSG = oxidized glutathione; MPO = myeloperoxidase; NOX2,= NADPH oxidase 2; COX2 = cyclooxygenase-2; iPLA2β = calcium-independent phospholipase A2β; PL = phospholipid; A = arachidonic acid; TG = triacylglycerol; PE = phosphatidylethanolamine; HO = hydroxide; H2O2, = hydrogen peroxide; LPE = lyso-phosphatidylethanolamine; PGE2 = prostaglandin E2; PE-PGE2 = esterified prostaglandin E2; tr = truncated; ox = oxidized; HSP70 = heat shock protein 70; pMHC = MHC class I molecule. Created with Biorender.com