What is NETosis (Neutrophil Extracellular Trap formation)?

NETosis: A Distinct Form of Neutrophil Cell Death

NETosis is a specialized form of cell death unique to granulocytic cells (primarily neutrophils) characterized by the release of neutrophil extracellular traps (NETs) - web-like structures composed of nuclear proteins, chromatin, histones, and granular antimicrobial proteins that function as microbicidal structures. 1

Key Characteristics of NETosis

NETosis has several distinctive biochemical and morphological features:

• Cellular restriction: Occurs primarily in neutrophils and eosinophils 1
• Morphological changes: Involves massive vacuolization of the cytoplasm, rapid chromatin decondensation, and breakdown of both nuclear and granular membranes 1
• Biochemical pathway independence: Insensitive to caspase inhibitors and necrostatin-1, distinguishing it from apoptosis and regulated necrosis 1
• Key dependencies:
  • Requires NADPH oxidase-mediated superoxide generation
  • Depends on components of the autophagic machinery
  • Involves histone citrullination via peptidylarginine deiminase 4 (PAD4) 1

NET Formation Mechanisms

Two primary mechanisms of NET formation have been identified:

1. Vital NETosis: NETs are generated by viable neutrophils without cell death

   • Occurs in response to physiological stimuli like granulocyte-macrophage colony-stimulating factor (GMCSF) or complement fragment C5a
   • NET release occurs rapidly (30-60 minutes) after stimulation with IL-8 and lipopolysaccharide
   • Neutrophils remain viable (don't take up exclusion dyes) 1, 2

2. Suicidal NETosis: Involves neutrophil death with NET release

   • Typically triggered by non-physiological stimuli like phorbol-12-myristate-13-acetate
   • Results in cell death concurrent with NET formation 1, 2

Important Distinctions

It's crucial to understand that:

• NET formation and neutrophil death are not always linked - NETosis can occur without NET release, and NETs can be generated without cell death 1
• NETosis shares biochemical features with both autophagic cell death and regulated necrosis, but is distinct from both 1
• Current research suggests NETosis may be a unique cell death mechanism rather than a variant of existing pathways 1

Physiological and Pathological Roles

NETs play important roles in:

• Host defense: Trapping and killing pathogens as part of innate immunity 3
• Pathological conditions: Dysregulated NET formation contributes to:
  • Autoimmune diseases (SLE, rheumatoid arthritis, ANCA-associated vasculitis) 4
  • Cardiovascular diseases and thrombosis 1, 3
  • Sepsis and inflammatory conditions 3, 5
  • Cancer progression 3

Clinical Relevance

Understanding NETosis is important because:

• It represents a novel antimicrobial strategy distinct from phagocytosis
• Excessive or dysregulated NETosis contributes to tissue damage and inflammation
• NETs are increasingly recognized as therapeutic targets in various inflammatory and autoimmune conditions 3, 4
• Monitoring NET formation may provide biomarkers for disease activity 4

NETosis research continues to evolve, with ongoing investigations to determine whether it represents a truly unique cell death mechanism or a specialized variant of existing pathways 1.