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.

Keywords: Autoimmune disease; Cardiovascular disease; Citrullination; Metabolic disease; Neutrophil extracellular traps.

Fig. 1

Citrullination in chronic diseases. Citrullination can be viewed as the key process involved in the pathogenesis of many chronic diseases including RA, IBD, or periodontitis.

Fig. 2

Excessive ACPA formation could result in the loss of immune tolerance. ACPAs may accumulate in the synovium of even healthy individuals, until certain threshold is surpassed. Then, neutrophil recruitment into synovial joints ensues accompanied by NET formation. NETs contribute to tissue damage, in turn leading to swelling, stiffness, pain, and ultimately, bone erosion. ACPAs, anti-citrullinated peptide antibodies; NETs, neutrophil extracellular traps.

Fig. 3

Hypothetical mechanism of the induction of immune response of P. gingivalis by PPAD-mediated citrullination. P. gingivalis, a frequent colonizer of the oral cavity of periodontitis patients expresses its own PPAD theoretically capable of producing citrullinated proteins with new epitopes which were not encountered before by immune cells and thereby potentially causing substantially higher immunoreactivity (b) compared to the state with no P. gingivalis infection (a). PAD, peptidyl arginine deiminase.

Fig. 4

NETs may exacerbate MetS. The accumulation of NETs may be detrimental in MetS, as NETs were documented to increase the risk for thrombosis and delayed fibrinolysis. In addition, NETs formed in diabetic mice were seen to hamper wound healing. NET, neutrophil extracellular trap.

Fig. 5

a, bAbnormal NET presence is associated with cardiovascular disease. With the progression of atherosclerosis, migration of neutrophils to the site of microinjury can be observed. The accumulation of neutrophils and NETs may serve as a scaffold facilitating thrombogenesis, for instance via the action of histones H3 and H4. Over time, this may eventually lead to vein occlusion. NET, neutrophil extracellular trap.

Fig. 6

Changes in the brain leading to demyelination and axon damage. Citrullination normally occurs also in the brain; however, the percentage amount of citrullinated proteins such as MBP, GFAP, or MOG is associated with the severity of MS. Via citrullination, new epitopes are formed which leads to neutrophil infiltration, NET formation, demyelination of the myelin sheath, and ultimately, failure in signal transduction causing, and ever-increasing degree of disability. GFAP, glial acidic fibrillary protein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; NET, neutrophil extracellular trap.