Mitochondrial DNA as a Damage-Associated Molecular Pattern in Stored Blood: Mechanisms of Transfusion-Induced Sterile Inflammation.

Transfusion of stored red blood cells (RBCs) is a life-saving intervention in trauma, surgery, and critical care. However, storage-induced alterations, collectively termed "storage lesions," lead to the accumulation of bioactive mediators, including mitochondrial DNA (mtDNA), which functions as a potent damage-associated molecular pattern (DAMP). mtDNA released from residual leukocytes, platelets, and extracellular vesicles during storage activates innate immune pathways via TLR9, cGAS-STING, and NLRP3 inflammasome signaling. This triggers neutrophil extracellular trap (NET) formation, monocyte/macrophage activation, platelet aggregation, and endothelial dysfunction, contributing to transfusion-related complications such as transfusion-related acute lung injury (TRALI), transfusion-related immunomodulation (TRIM), microvascular thrombosis, and organ injury. Mechanistic understanding of mtDNA-mediated sterile inflammation highlights multiple intervention points, including improved storage conditions, leukoreduction, mtDNA removal, modulation of extracellular vesicles, and pharmacologic inhibition of downstream immune pathways. Integrating these strategies offers the potential to mitigate transfusion-induced inflammatory complications and improve patient outcomes.