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Fig. 3 | Military Medical Research

Fig. 3

From: Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

Fig. 3

Four types of cell death in sepsis. Apoptosis: Apoptosis is activated in either the extrinsic or the intrinsic pathway. The extrinsic pathway is triggered by the Fas/FasL pathway after infection. The death receptor Fas activates caspase-8 by binding to the Fas ligand that is expressed on activated T lymphocytes during cellular immunity followed by activation of caspase-3 to trigger the execution pathway of apoptosis. In the intrinsic pathway, death stimuli including DNA damage and the accumulation of misfolded proteins break the balance between proapoptotic and antiapoptotic signals mediating mitochondrial outer membrane permeabilization after which cytochrome C is released from mitochondria and forms an apoptosome with Apaf-1. The apoptosome activates caspase-9 and finally activates caspase-3. The pro-apoptotic protein Bim accelerates apoptosis while the anti-apoptotic protein Bcl-2 inhibits apoptosis. Pyroptosis: In the classical pathway, the inflammasome complex activates caspase-1 upon simulating PAMPs and DAMPs. Caspase-1 promotes the release of pro-inflammatory cytokines such as IL-1β IL-18 and HMGB1 and then cleaves gasdermin into GSDMD. GSDMD aggregates into a pore on the cell membrane. In the non-classical pathway, LPS activates caspase-4, caspase-5 and caspase-11 which cleave gasdermin into GSDMD to form the pore and drive pyroptosis. Autophagy: Atg 8/12 systems activate the phagophore to form the autophagosome. The autophagosome fuses with the lysosome and further form an autolysosome. Lysosomal enzymes degrade misfolded proteins and damaged organelles in autolysosomes and enter the recycling process. Ferroptosis: Ferroptosis is a ROS-dependent form of cell death defined by iron-dependent accumulation and lipid peroxides that is resulted from an imbalance between the synthesis of oxidants and antioxidants. At the core process, PUFAs and lipids containing PUFAs are particularly sensitive to oxidation by enzymes and nonenzymatic processes such as iron-dependent Fenton reactions to form lipid hydroperoxides that can produce toxic lipid free radicals (e.g., alkoxyl radicals) in the presence of iron. Furthermore, by taking protons from neighboring PUFAs, these free radicals might initiate a new round of lipid oxidation and spread oxidative damage. GPX4 functions as a phospholipid hydroperoxidase in the redox system to reduce phospholipid hydroperoxide production and plays an anti-ferroptosis role. The enzyme HO-1 can accelerate the formation of a labile iron pool and further promote lipid peroxidation. GSDMD gasdermin-D, LPS lipopolysaccharide, Atg autophagy-related gene, ROS reactive oxygen species, PUFA polyunsaturated fatty acid, LIP labile iron pool, GPX4 glutathione peroxidase 4, HMGB1 high mobility group box 1, IL interleukin. Part of the autophagy was created partially utilizing the templates on BioRender.com as a reference

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