Viral mimetic poly(I:C) induces neutrophil extracellular traps via PAD4 to promote inflammation and thrombosis.

ABSTRACT

Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(IC)] is known to induce inflammation and thrombosis. However, whether and how poly(IC) modulates NETs remains unclear. Here, we have demonstrated that poly(IC) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(IC) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(IC)-induced NETs formation and release. In addition, BB-CLA abrogated poly(IC)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(IC)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(IC) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.