STING Modulates CD4 T Cell Necroptosis via Activation of PARP-1/PAR Following Acute Systemic Inflammation

Background: Regulated cell death profoundly affects on the progress of inflammatory and immune responses in various acute inflammatory diseases, as seen in sepsis and trauma. However, the mechanisms underlying CD4 T cells death have not yet been fully addressed. Results: We demonstrated that interferon genes (STING) promoted excessive Poly (ADP-ribose) polymerase 1 (PARP-1) activity stimulated by endotoxin, which in turn induced apoptosis-inducing factor (AIF)-independent but PARP-1 dependent programmed cell death. Elevated PARP-1 activity triggered a cascade of molecular events, including PAR polymer release from the nucleus and the nicotinamide adenine dinucleotide (NAD + ) and ATP depletion. Interestingly, translocation of AIF, a biochemical signature for PARP-1-dependent parthanatos, was not observed in the present study, suggesting a non-canonical mechanism of CD4 T cells parthanatos. In this study, we also identify a STING-mediated mechanism of necroptosis in CD4 T cells in septic animals. Furthermore, we revealed wider effects of STING on the immune functions of CD4 T cells when PARP-1 gene inhibited. Conclusions: These findings reveal that STING signaling and targeting PARP-1/PAR pathway in CD4 T cells may present a new therapeutic strategy for the treatment of acute systemic inflammatory diseases.