NETs Enhance STING To Promote Surgical Adhesion

Abstract

Background Postoperative adhesion (PA) following abdominal surgery may cause bowel obstruction, chronic pain, infertility, or even death. Knowledge of adhesion biology is limited, and preventive agents in clinical trials have failed to achieve efficacy. Results In the present study, we showed that neutrophils accumulate in the injured peritoneum at early stage of PA, and neutrophils within the ischemic buttons undergo cell death and form neutrophil extracellular traps (NETs) that contribute to PA. Neutrophil depletion reduces adhesion burden at 7 days after adhesion induction. Peptidylarginine deiminase 4 (PAD4), an essential enzyme for NET formation, is increased in ischemic buttons. Degradation of NETs by DNase 1 and suppression of NET formation by pharmacologic inhibition of PAD4 alleviated adhesion burden, collogen deposition and fibrosis formation. Mechanistically, administration of DNase I and PAD inhibitor reduces STING-mediated inflammatory response. STING deficiency attenuates adhesion burden, collogen deposition, and α-SMA production in the adhesive tissues at 7 days after surgery. Conclusions Collectively, our findings reveal NETs/STING signaling as a therapeutic target to prevent PA.

Neutrophil Extracellular Traps: A Crucial Factor in Post-Surgical Abdominal Adhesion Formation

“…Additionally, research involving gastric cancer patients post-surgery shows that increased NET production by low-density neutrophils facilitates tumor cell attachment and growth, proposing that DNase treatment to disrupt these NETs could prevent peritoneal recurrence [ 22 ]. Moreover, investigations reveal that early-recruited neutrophils release NETs that activate the STING-associated inflammatory response, with interventions that disrupt NETs and inhibit STING signaling markedly reducing adhesion burden, thus identifying NET/STING pathways as potential therapeutic targets [ 24 ]. Similarly, evidence from murine models indicates that NETs are crucial in forming peritoneal adhesions, with DNase treatments significantly reducing these adhesions, suggesting potential therapeutic approaches pending further clinical validation [ 23 ].…”