Fig. 5

The complexity of AM death Regulation following infection, trauma, and HS. LPS, an important PAMP molecule derived from Gram negative bacteria acting through TLR4 promotes AM necroptosis. However, DAMP molecules released from tissue damage, which is a resultant of severe trauma and HS, significantly influence the regulation of AM death. For example, DAMP molecule HMGB1 acting through cell surface RAGE and MyD88-dependent pathway (as illustrated in Fig. 3) ameliorates the TLR4-mediated AM necroptosis. On the other aspect, HMGB1triggers RAGE-dynamin-dependent endocytosis of HMGB1, which promotes AM pyroptosis. HMGB1/TLR4 signaling upregulates NOD2 expression in AM and sensitizes them to subsequent NOD2 ligand MDP to induces autophagy in AM, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. DAMP molecule CIRP acts through TLR4-MyD88 signaling to induce mtDNA fragmentation in AM, via a pathway in which NADPH oxidase-derived ROS served as a major mediator for the induction of endonuclease G, which, in turn, directly mediates mtDNA fragmentation. Fragmented mtDNA then triggered AM autophagy and necroptosis through separate signaling pathways, although autophagy also suppressed AM necroptosis, to attenuate propagation of local inflammation. Therefore, AM autophagy represents an intracellular negative regulation of AM death, whereas, pyroptosis serves as a dominant AM death form in a condition combined with infection, trauma and hemorrhage