Figure 2. Pathways of NET formation and targets for therapies.

Stimulation of neutrophils in an individual genetically predisposed to SLE by various stimuli (microbial, autoantibodies, cell products, etc.) mobilizes calcium from the endoplasmic reticulum that results in activation of protein kinase C (PKC) and NADPH and/or mitochondrial ROS production. This leads to migration of granule protein to the nucleus and activation of peptidylarginine deiminase-4 (PAD4), which induce citrullination, resulting in changes in electrostatic interactions of DNA and histones, which disrupt chromatin’s structure and promote decondensation of nuclear material. This process is followed by degradation of nuclear and granule membranes with mixture of granular protein with chromatin and eventual extrusion of NETs into the extracellular space. Gasdermin D (GSDMD) is implicated in some forms of NET formation, in which ROS-mediated release of neutrophil elastase (NE) processes GSDMD, which further facilitates release and activation of NE. GSDMD also localizes to the plasma membrane to form pores that promote cell lysis to release NETs. Possible therapies targeting critical steps in this pathway (represented by blunt arrows) may be beneficial for SLE. FcγR, Fcγ receptor; IFNAR, type I IFN receptor; JAK, Janus kinases; MPO, myeloperoxidase; TLR, Toll-like receptor.