Regulation of Neutrophil Extracellular Trap Formation by Anti-Inflammatory Drugs

Abstract

The formation of neutrophil extracellular traps (NETs) is a newly described phenomenon that increases the bacteria-killing ability and the inflammatory response of neutrophils. Because NET generation occurs in an inflammatory microenvironment, we examined its regulation by anti-inflammatory drugs. Treatment of neutrophils with dexamethasone had no effect, but acetylsalicylic acid (ASA) treatment prevented NET formation. NETosis was also abrogated by the presence of BAY 11-7082 [(E)-3-[4-methylphenylsulfonyl]-2-propenenitrile] and Ro 106-9920 [6-(phenylsulfinyl)tetrazolo [1,5-b]pyridazine], two structurally unrelated nuclear factor-kB (NF-kB) inhibitors. The decrease in NET formation mediated by ASA, BAY-11-7082, and Ro 106-9920 was correlated with a significant reduction in the phosphorylation of NF-kB p65 subunit, indicating that the activation of this transcription factor is a relevant signaling pathway involved in the generation of DNA traps. The inhibitory effect of these drugs was also observed when NET generation was induced under acidic or hyperthermic conditions, two stress signals of the inflammatory microenvironment. In a mouse peritonitis model, while pretreatment of animals with ASA or BAY 11-7082 resulted in a marked suppression of NET formation along with increased bacteremia, dexamethasone had no effect. Our results show that NETs have an important role in the local control of infection and that ASA and NF-kB blockade could be useful therapies to avoid undesired effect of persistent neutrophil activation.

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

“…PI3K generates phosphatidylinositol (3,4,5)-trisphosphate, which influences the transcription factor NF-kB (109). NF-kB activation leads to transcription of proinflammatory genes and is relevant in the signaling leading to NET release (110). Moreover, FIGURE 6.…”

Thrombosis: tangled up in NETs

“…92,93 Interestingly, aspirin can also inhibit NETosis in vitro. 94 Preventing Weibel-Palade body release, for example with agents that increase nitric oxide generation 95 or otherwise interfere with endothelial VWF/P-selectin secretion, 96 or targeting platelet-VWF interactions would both prevent platelets and neutrophils from tethering onto the vessel wall and their possible recruitment of other platelets and neutrophils on activation. The A1 domain of VWF binds to glycoprotein Ib on platelets, promoting their adhesion.…”

New perspectives on the thrombotic complications of haemolysis

“…DNase treatment and heparin administration dismantle the NET scaffold and prevent thrombus formation (Fuchs et al, 2010). Furthermore, aspirin and NF-jB inhibitors block NET formation (Lapponi et al, 2013). P-selectin inhibition also decreases neutrophil recruitment, platelet-neutrophil interactions, and NET formation (von Bruhl et al, 2012), thereby targeting multiple pathways in the pathogenesis of thrombosis.…”