The Citrullination-Neutrophil Extracellular Trap Axis in Chronic Diseases

Abstract

Citrullination of proteins is crucial for the formation of neutrophil extracellular traps (NETs) – strands of nuclear DNA expulsed in the extracellular environment along with antimicrobial proteins in order to halt the spread of pathogens. Paradoxically, NETs may be immunogenic and contribute to inflammation. It is known that for the externalization of DNA, a group of enzymes called peptidyl arginine deiminases (PADs) is required. Current research often looks at citrullination, NET formation, PAD overexpression, and extracellular DNA (ecDNA) accumulation in chronic diseases as separate events. In contrast, we propose that citrullination can be viewed as the primary mechanism of autoimmunity, for instance by the formation of anti-citrullinated protein antibodies (ACPAs) but also as a process contributing to chronic inflammation. Therefore, citrullination could be at the center, connecting and impacting multiple inflammatory diseases in which ACPAs, NETs, or ecDNA have already been documented. In this review, we aimed to highlight the importance of citrullination in the etiopathogenesis of a number of chronic diseases and to explore the diagnostic, prognostic, and therapeutic potential of the citrullination-NET axis.

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…Neutrophils also contribute to immune surveillance by forming neutrophil extracellular traps (NETs), web-like structures composed of DNA and antimicrobial proteins, which can capture and neutralize pathogens, including HBV[ 56 ]. For example, Maronek and Gardlik[ 57 ] explained that patients diagnosed with liver cirrhosis demonstrate a reduced capacity of neutrophils to discharge NETs. This impairment concomitates a decline in CD69 and CD80 expression.…”

Recent advances in characterization of citrullination and its implication in human disease research: From method development to network integration

“…PAD2 and PAD4 are the two main isozymes determined to mediate citrullination in RA, both of which have been localized in neutrophils [102]. Inflammation is one of the trademark characteristics of RA and results from atypical citrullination, which promotes the formation of NETs, a network of extracellular strings of DNA that bind pathogenic microbes [103,104]. It has also been found that citrullinated histones from neutrophils were routinely targeted by ACPAs, suggesting that increased histone citrullination could be linked to increased autoimmune response [105].…”