Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

Abstract

Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…Interestingly, a similar EV-mediated export of deiminated histones, as observed in cow serum-EVs in the current study, was recently identified in the naked mole-rat, an animal with unusual immunological and metabolic traits [98], as well as in alligator, also an animal with unusual antimicrobial, including anti-viral responses [93]. Deiminated histone H3 is commonly used as an indicator for neutrophil extracellular trap formation (NETosis) [31,244], which has been related to PAD4 and implicated in anti-viral responses in cattle respiratory syncytial virus disease [42], in response to parasitic infections in cattle [245][246][247] as well as in response to certain antibiotics [248]. Interestingly, in crocodilians, extracellular histones H2A and H4 have been identified to act as inhibitors of viral (HIV) infection in vitro [249], although roles for post-translational deimination were not assessed.…”

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

“…Both neutrophil elastase (NE) and peptidyl arginine deiminiase‐4 (PAD4) have been implicated in NET formation, 50–53 although there is disagreement on the conditions and requirements for their involvement (for reviews, see [47, 48, 54]). PAD4 is extensively studied in the context of NET formation, where it mediates citrullination of histones, disrupts nucleosomes and allows chromatin unspooling and NET formation (for review see [55]). NE is also known to directly cleave extracellular IL‐1β at tissue damage sites 56,57 although reports show this processing may actually inactivate the cytokine 58 .…”

Neutrophil extracellular traps in COVID-19

“…Somewhat unexpectedly, Cit-H3 did not correlate well with the other two markers, but did associate strongly with platelet levels. It is believed that the predominant driver of histone citrullination (i.e., production of Cit-H3) in NETs is the enzyme peptidlyarginine deiminase 4 (PAD4) (38). However, neutrophils can be triggered to undergo NETosis by a variety of stimuli, and in vitro studies demonstrate that not all pathways to NETosis are equally reliant on PAD4 activity (39); for example, stimuli that lead to robust reactive oxygen species production may be relatively PAD4-independent (40).…”