Cold-inducible RNA-binding protein through TLR4 signaling induces mitochondrial DNA fragmentation and regulates macrophage cell death after trauma

摘要

Trauma is a major cause of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Macrophages (M Φ ) direct trauma-induced inflammation, and M Φ death critically influences the progression of the inflammatory response. In the current study, we explored an important role of trauma in inducing mitochondrial DNA (mtDNA) damage in M Φ and the subsequent regulation of M Φ death. Using an animal pseudo-fracture trauma model, we demonstrated that tissue damage induced NADPH oxidase activation and increased the release of reactive oxygen species via cold-inducible RNA-binding protein (CIRP)–TLR4–MyD88 signaling. This in turn, activates endonuclease G, which serves as an executor for the fragmentation of mtDNA in M Φ . We further showed that fragmented mtDNA triggered both p62-related autophagy and necroptosis in M Φ . However, autophagy activation also suppressed M Φ necroptosis and pro-inflammatory responses. This study demonstrates a previously unidentified intracellular regulation of M Φ homeostasis in response to trauma.