Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe?

The discovery of neutrophil extracellular traps in 2004 opened a fascinating new chapter in immune‐mediated microbial killing. Brinkman et al. demonstrated that neutrophils, when catastrophically stimulated, undergo a novel form of programmed cell death (neutrophil extracellular trap formation) whereby they decondense their entire nuclear chromatin/DNA and release the resulting structure into the cytoplasm to mix with granule‐derived antimicrobial peptides before extruding these web‐like structures into the extracellular environment. The process requires the activation of the granule enzyme peptidyl arginine deiminase‐4, the formation of reactive oxygen species (in particular hypochlorous acid), the neutrophil microtubular system and the actin cytoskeleton. Recent work by Yousefi et al. demonstrated that exposure to different agents for shorter stimulation periods resulted in neutrophil extracellular trap release from viable granulocytes, and that such neutrophil extracellular traps comprised mitochondrial DNA rather than nuclear DNA and were also capable of microbial entrapment and destruction. Deficiency in NADPH‐oxidase production (as found in patients with chronic granulomatous disease) results in an inability to produce neutrophil extracellular traps and, along with their failure to produce antimicrobial reactive oxygen species, these patients suffer from severe, and sometimes life‐threatening, infections. However, conversely the release of nuclear chromatin into tissues is also potentially autoimmunogenic and is now associated with the generation of anti‐citrullinated protein antibodies in seropositive rheumatoid arthritis. Other neutrophil‐derived nuclear and cytoplasmic contents are also pathogenic, either through direct effects on tissues or via autoimmune processes (e.g. autoimmune vasculitis). In this review, we discuss the plant origins of a highly conserved innate immune method of microbial killing, the history and biology of neutrophil extracellular traps and their role in defence and in human diseases. We attempt to resolve areas of controversy and propose roles for excess neutrophil extracellular trap release from hyperactive/reactive neutrophils and for the unique peptidyl arginine deiminase enzyme of Porphyromonas gingivalis in the pathogenesis of periodontitis, and subsequently a role for periodontitis/the peptidyl arginine deiminase enzyme of P. gingivalis in the causal pathway of autoimmune diseases such as rheumatoid arthritis. We pro