Development of „smart“ amplifiers of NET formation and modulators of redox signalling.

Neutrophil extracellular traps (NETs) are a double-edged sword, being able to contribute to hyperinflammation and tissue damage but also to mediate resolution of inflammation (Euler et al, Biochem Soc Trans 2019; Boeltz et al. Cell Deth Differ 2019; Ackermann et al, Cell Death Differ 2021). Thus, while NET inhibitors can be an efficient protection against NET-mediated tissue damage, therapeutic amplification of NET formation, e.g. via triggering the formation of reactive oxygen species (ROS), is a potential way to induce resolution of inflammation. We have previously shown that induction of NADPH oxidase 2 (NOX2)-derived ROS can ameliorate experimental lupus (Kienhöfer et al., JCI Insight 2017; Hahn et al, Redox Biol 2019). The major mechanism underlying this therapeutic effect involve proteolytic degradation of cytokines and antibody modifications induced by aggregated NETs (Schauer et al. Nat Med 2014; Hahn et al., FASEB J 2019). However, since autoimmune diseases are associated with impaired function of NOX2, NOX2-activators might have an only limited efficacy. ROS amplifiers that induce NET formation independently of NOX2 are therefore needed. A possible solution is the use of aminoferrocene-based prodrugs (ABP), which are powerful NOX2-independent ROS amplifiers both in vitro and in vivo in rodents (Reshetnikov et al., Frontiers Immunol 2018). In a project funded by the European Commission (EU-H2020-FETOpen-861878 NeutroCure, www.neutrocure.eu) we aim to establish and refine treatment protocols with next generation NOX2-dependent or -independent NET inducers.

Related publications: 

Ackermann et al, Cell Death Differ 2021 (PMID 34031543)

Boeltz et al., Cell Death Diff (PMID 30622307)

Euler et al, Biochem Soc Trans (PMID 31754705)

Griffiths et al., Free Rad Biol Med 2018 (PMID 29550327)

Hahn et al, FASEB J 2019 (PMID 30130433)

Hahn et al, Redox Biol 2019 (PMID 31349119)

Schauer et al, Nat Med 2014 (PMID 24784231)

Main responsible: Emely Jane Hoffmann