Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury

• DOI: 10.1164/rccm.201706-1161oc
• Publication Date: 2017-10-20T13:46:04Z
• Authors: Meghan J. Hotz; Danielle Qing; Michael G. S. Sha...; Peggy Zhang; Hilary Faust; Neal Sondheimer; Stefano Rivella; G. Scott Worthen; Nilam S. Mangalmurti
• Keywords: TLR9; Toll-Like Receptor 9; CpG site

Rationale: Potentially hazardous CpG-containing cell-free mitochondrial DNA (cf-mtDNA) is routinely released into the circulation and associated with morbidity mortality in critically ill patients. How body avoids inappropriate innate immune activation by cf-mtDNA remains unknown. Because red blood cells (RBCs) modulate responses scavenging chemokines, we hypothesized that RBCs may attenuate CpG-induced lung inflammation through direct of DNA.Objectives: To determine mechanisms CpG-DNA binding to effects RBC-mediated on inflammation.Methods: mtDNA murine was measured under basal conditions after systemic inflammation. content human from healthy control subjects trauma patients measured. Toll-like receptor 9 (TLR9) expression TLR9-dependent were determined. A model RBC transfusion CpG-DNA–induced injury used investigate role mitigating vivo.Measurements Main Results: Under conditions, bind CpG-DNA. The plasma-to-RBC ratio low naive mice volunteers but increases inflammation, demonstrating majority RBC-bound homeostatic unbound fraction during express TLR9 TLR9. Loss increased vivo.Conclusions: homeostatically mtDNA, essential Our data suggest a for regulating disease states where elevated, such as sepsis trauma.