PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock

Abstract

Key Points Absence of NETs in PAD4−/− mice did not affect bacteremia in polymicrobial sepsis produced by cecal ligation and puncture. PAD4-deficiency improved outcome in lipopolysaccharide (LPS)-induced sepsis.

Histones as Mediators of Host Defense, Inflammation and Thrombosis

“…In the case of transfusion-related acute lung injury, platelet activation resulted in NET formation in blood and lungs and anti-histone antibody or DNase were protective [97]. As noted above, PAD4 gene-deleted mice which cannot citrullinate histones or form NETs were protected from LPS-induced sepsis physiology [68].…”

“…Mice lacking PAD4 cannot form NETs and had worse outcome in a model of necrotizing fasciitis infection [67]. In contrast, these mice had similar response to sepsis induced by cecal ligation and puncture and were partially protected from endotoxin-induced shock [68]. An interesting recent report raised some question about the importance of NETs in human defense against infection [69,70].…”

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

“…Initially, NETs were described as an antimicrobial strategy, but the tissue damaging potential of NETs has gained salient attention (11), with aberrant NET formation now being suggested to contribute extensively to the pathogenesis of sepsis (12), autoimmunity (13)(14)(15)(16), vascular inflammation (17), and thrombosis (18)(19)(20)(21). The release of NETs within the circulation, as well as their interaction with platelets and RBCs, has devastating procoagulant and prothrombotic consequences (18,19,(22)(23)(24).…”

Neutrophil Extracellular Traps - The Invisible Inflammatory Mediator in Fibrosis

“…A lot of research effort is required in order to delineate which NET components influence pathways that are implicated in fibrotic process, while their presence in fibrotic tissue and their ability to affect a key stage of the fibrotic response constitute them a potential therapeutic target. Moreover, the inhibition of NET generation as a therapeutic approach could provide a more efficient and less immunosuppresive alternative [19]. Targeting NETs alone or in combined therapies could offer more efficient treatment against fibrosis.…”