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Cell Death Dis. 2017 May 11;8(5):e2775. doi: 10.1038/cddis.2017.187.

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

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Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
University of Pittsburgh School of Arts and Science, Pittsburgh, PA 15213, USA.
Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China.
Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.
McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.


Trauma is a major cause of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Macrophages (Mφ) direct trauma-induced inflammation, and Mφ 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 Mφ and the subsequent regulation of Mφ 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 Mφ. We further showed that fragmented mtDNA triggered both p62-related autophagy and necroptosis in Mφ. However, autophagy activation also suppressed Mφ necroptosis and pro-inflammatory responses. This study demonstrates a previously unidentified intracellular regulation of Mφ homeostasis in response to trauma.

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