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The Importance of Immune Cells in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Andres Gonzalez Salazar, David J. Hackam
The relationship between neutrophils (PMNs) and NEC has been studied for the past 3 decades. Musemeche et al. initially concluded an important role for PMNs in NEC by depleting neutrophils with vinblastine in a platelet activator factor (PAF) and lipopolysaccharide (LPS) rat NEC model, which decreased the severity of intestinal injury (3). The role of PMNs in NEC received little attention, given the fact that histologic and flow cytometric evaluation of the human and mouse bowel with NEC is relatively PMN deficient (1). More recently, PMNs have been linked to the development of NEC through the formation of neutrophil extracellular traps (NETs). These are web-like structures made up of DNA that contain antimicrobial proteins and histones and are formed in the presence of virus, bacteria, and protozoa, where they bind to, immobilize, and eliminate microorganisms (4, 5). Studies have suggested that an excessive NET formation is crucial in the ischemic injury that ultimately leads to neutrophilic tissue damage (4). In both animal models and human neonates suffering from NEC, studies have demonstrated an increase in intestinal cell-free DNA (cfDNA) and neutrophilic proteins, markers of NET formation (5, 6). In further support of this association, more recent studies have hypothesized that impeding or dissolving NET formation may lead to reduced tissue injury and inflammation (7, 8). Treatment of mice NEC models with DNase1 and protein arginine deiminase (PAD), inhibitors of NETs, have been shown decreased NEC severity, further supporting these claims (9, 10).
The Role of Neutrophil Extracellular Traps in the Ocular System
Published in Current Eye Research, 2022
Yingsi Li, Luoying Xie, Wenjing Song, Meiting Huang, Yu Cheng, Shudi Chen, Yuan Gao, Xiaoming Yan
Conventional suicidal NETosis was initially found after PMA-induced NET formation.1 The activation of protein kinase C (PKC) by PMA results in a high level of cytoplasmic Ca2+via release from the endoplasmic reticulum. Due to Ca2+ influx, the Raf-MEK-ERK pathway is activated via the activation of NOX and the upregulation of anti-apoptotic proteins.19,20 The next important step is the generation of ROS, which are produced via a NOX-dependent or mitochondrial pathway.21,22 An ROS burst induces NE and MPO migration to the nucleus to collectively degrade histones and promote chromatin decondensation.21,23 Protein-arginine deiminase type 4 (PAD4) is a key nuclear enzyme in NET formation that drives histone 3 citrullination, and it is activated by Ca2+ influx.19,24 Rupture of the nuclear membrane allows the combination of granular proteins and DNA to form NETs, which are extruded into the extracellular compartment as the cell membrane disintegrates.20,25 This process ends with NET release and cell death and is also known as lytic NETosis (Figure 1).
Autoantibodies to protein-arginine deiminase (PAD) 4 in rheumatoid arthritis: immunological and clinical significance, and potential for precision medicine
Published in Expert Review of Clinical Immunology, 2019
Laura Martinez-Prat, Boaz Palterer, Gianfranco Vitiello, Paola Parronchi, William H. Robinson, Michael Mahler
The presence of autoreactive T- and B-cells and the production of autoantibodies are key features of RA, with Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) being the main two biomarkers. Yet, up to 60% of the early RA patients do not present these antibodies, often referred to as the serological gap [3]. Although the combination of ACPA and RF can increase the diagnostic efficiency [3], seronegative patients persist. Consequently, numerous studies aimed to identify novel biomarkers to further improve the diagnosis of RA [4]. In addition, biomarkers that aid in establishing prognosis, in patient stratification, in disease activity monitoring and in predicting response to treatment are desired. In this context, several novel autoantibodies have been described in RA patients over the past few years [4], including antibodies targeting carbamylated proteins (CarP) [5–8] and the protein-arginine deiminase (PAD) enzymes [9–12]. The PAD proteins are enzymes that catalyze the conversion of peptidyl-arginine into peptidyl-citrulline, a post-translational modification (PTM) known as citrullination or deimination, which is an important part in the pathogenesis of RA. In addition to their role in citrullination, three members of the PAD family of enzymes have been recently identified as autoantigens in RA, including PAD2, PAD3, and PAD4 [11–13], and among them, antibodies to PAD4 are the most characterized. In the last few years, PAD enzymes captured growing attention due to the cumulative understanding of their role in the pathogenesis of RA and the potential to block PAD activity as a novel treatment strategy [14–16]. The objective of this review is to provide an overview of the current understanding on anti-PAD4 antibodies in RA, including their role in pathogenesis, their clinical significance and their potential for precision medicine (PM) approaches.
Rituximab induces a flare-up of activated neutrophil extracellular traps under in vitro conditions
Published in Immunopharmacology and Immunotoxicology, 2022
Joerg Hoffmann, Samira Roesner, Andreas Neubauer
Circulating neutrophil granulocytes are the most frequent leukocytes in the peripheral blood and part of the innate immune system. In the acute phase of infection, neutrophils migrate toward the site of inflammation and can resolve infections by phagocytosis of pathogens and degranulation of anti-microbials [1]. Next to phagocytosis and degranulation neutrophils can release neutrophil extracellular traps (NET) [2]. The release of NET is induced by infection with different pathogens, including Gram-positive/-negative bacteria and fungi [2–5]. It can be triggered under laboratory conditions by stimulation with phorbol 12-myristate 13 acetate (PMA) and bacterial products such as ionomycin and lipopolysaccharide (LPS) [2,6]. Subsequently, stimulation leads to the assembly and activation of NADPH oxidase complex and formation of reactive oxygen species (ROS) [7]. ROS production results in the activation of protein–arginine deiminase 4 (PAD4) which converts arginine in histones to citrulline. PAD4 activation is crucial for NET formation [8]. Together with translocated intranuclear neutrophil elastase and myeloperoxidase (MPO), PAD4 induce unfolding of chromatin [8–10]. Finally, the nuclear membrane disrupts, and NET are released. Further molecular aspects of NET formation are reviewed in Liu et al. [11]. NET consist of decondensed chromatin fibers with wrapped histones and are further compounded by proteases, granule components and other cytosolic proteins [2]. This extracellular network has antimicrobial properties even before engulfing pathogens [2]. The process of NET release and subsequent cell death was called NETosis [12]. However, Yipp et al. showed that in some circumstances anuclear neutrophils after NETosis were still able to phagocyte bacteria (vital NETosis) [5]. In a recent consensus review, “NET formation” instead of “NETosis” was the preferred term because the process can end either with or without cell death [13].