Neutrophil extracellular traps (NETs) are antimicrobial structures, but excessive NET formation is now implicated in tissue injury in several diseases. Which enzyme, expressed on the outer cell membrane of activated neutrophils, initiates NET formation by citrullinating histones?

• A Myeloperoxidase (MPO)
• B Neutrophil elastase (NE)
• C Peptidylarginine deiminase 4 (PAD4) ✓
• D Matrix metalloproteinase-8 (MMP-8)

Explanation

PAD4 (peptidylarginine deiminase 4) is a nuclear enzyme that citrullinates arginine residues on histones H3 and H4, causing chromatin decondensation — the first step in vital NETosis. PAD4 activation requires calcium influx and upstream signalling; citrullinated histone H3 (citH3) is a biomarker of NET formation. Neutrophil elastase translocates from granules to the nucleus and also participates in chromatin decondensation, while MPO generates reactive oxygen species that further amplify NET formation. NETs are implicated in thrombosis in COVID-19, lupus, and sepsis.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.