Abstract Number: PB1289
Meeting: ISTH 2022 Congress
Background: Neutrophil Extracellular Traps (NETs) are scaffolds of extracellular fibers, primarily composed of unfolded double-stranded DNA and granular enzymes, that are released from activated neutrophils. NETs have a role in host defense; however, excessive NET formation contributes to inflammatory and thrombotic diseases. The histone citrullinating protein peptidyl arginine deiminase 4 (PAD4) and the pore-forming protein gasdermin d (GSDMD) have been proposed to play important roles for NET formation.
Aims: In this study, we aimed to study the role of GSDMD and PAD4 in NET formation in experimental models of septicemia and sterile neutrophilia.
Methods: We generated Gsdmd-/- and Pad4-/- knock-out mice on a Dnase1-/-Dnase1l3-/- deficient background. We induced sterile neutrophilia and septicemia in Dnase1-/-Dnase1l3-/-, Dnase1-/-Dnase1l3-/-Gsdmd-/- and Dnase1-/-Dnase1l3-/-Pad4-/- mice using a hepatic expression vector encoding the gene for G-CSF and by injecting LPS and heat-killed E. coli, respectively. The formation of NET clots in vitro from isolated murine neutrophils was tested using different activators and pharmacological inhibitors.
Results: Dnase1-/-Dnase1l3-/-Gsdmd-/- and Dnase1-/-Dnase1l3-/-Pad4-/- mice were not protected from death during sterile neutrophilia or septicemia. Histological analysis of lung sections showed that NET-derived clots occluded blood vessels in both mouse strains. Furthermore, we found that the genetic or pharmacological inhibition of GSDMD blocks in vitro NET formation in PMA-activated murine neutrophils.
Conclusion(s): Taken together, we unexpectedly found that GSDMD deficiency blocked PMA-induced NET formation in vitro, however it did not inhibit NET formation in our two independent in vivo models of sterile neutrophilia and septicemia.
To cite this abstract in AMA style:Englert H, Rangaswamy C, Divivier M, Göbel J, Hermans-Borgmeyer I, Mowen K, Fuchs T, Renné T. Gasdermin D is dispensable for NET formation in vivo [abstract]. https://abstracts.isth.org/abstract/gasdermin-d-is-dispensable-for-net-formation-in-vivo/. Accessed March 4, 2024.
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