![Schematic of proposed mechanisms. (A) Our data show that SCD neutrophils produce increased NETs, which are exacerbated upon stimulation (eg, ionomycin), leading to increased phosphorylation of NET specific kinases (ERK and Akt), which has been shown to result in histone citrullination and inhibition of apoptosis via upregulation of antiapoptotic proteins (eg, Mcl-133 [prothrombotic state]). Peptidylarginine deiminase 4 (PAD4) forms a complex with intracellular calcium to catalyze histone citrullination.31 NET stimuli activate PKC, PLC, and PI3K,33 which in turn activate ERK and AKT, resulting in calcium-PAD4 complex formation, which catalyzes histone citrullination. (B) We found that AnxA1Ac2-26 interacts with Fpr2/ALX, suppressing ERK and Akt phosphorylation, preventing histone citrullination, and enabling apoptosis by activating caspase-3 (proresolving state). Mcl-1, myeloid cell leukemia protein-1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC, protein kinase C; PLC, phospholipase C.](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/137/11/10.1182_blood.2020009166/5/bloodbld2020009166f5.png?Expires=1743567084&Signature=WsSffT~E3eV7qY-fUMFUmMI01lOPg8-apD6dI5HTt~6Jm4R6rxMRbMutVeYwTbjfm6x8pG7cG~Z4qWjV~29zvsthP15pY4fhKvw4IFGHg58pcEcncDWUTYtI0-VyvHr-pUcRKH8Biful29Rnj2vH18rAPdSLsnE7H7T8BnI86o~JurM19Yn~AsMqcpBMKA5XJT2qlzCyxlru004m46WgAc9b26nBuJgcivhkMmqLSTl9Z7QRs3EJqpmIkSPaB7uswhgwK8oOSoaZpWXbgVJOMj2z-OXQOzKXnjA0cgr0Jw2Viy9C-awSdLDEOVDV9BJjshE9-~H7-DUkMtl9S~7dUw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Schematic of proposed mechanisms. (A) Our data show that SCD neutrophils produce increased NETs, which are exacerbated upon stimulation (eg, ionomycin), leading to increased phosphorylation of NET specific kinases (ERK and Akt), which has been shown to result in histone citrullination and inhibition of apoptosis via upregulation of antiapoptotic proteins (eg, Mcl-133 [prothrombotic state]). Peptidylarginine deiminase 4 (PAD4) forms a complex with intracellular calcium to catalyze histone citrullination.31 NET stimuli activate PKC, PLC, and PI3K,33 which in turn activate ERK and AKT, resulting in calcium-PAD4 complex formation, which catalyzes histone citrullination. (B) We found that AnxA1Ac2-26 interacts with Fpr2/ALX, suppressing ERK and Akt phosphorylation, preventing histone citrullination, and enabling apoptosis by activating caspase-3 (proresolving state). Mcl-1, myeloid cell leukemia protein-1; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC, protein kinase C; PLC, phospholipase C.