NETs: the missing link between cell death and systemic autoimmune diseases?

Abstract

For almost 20 years, apoptosis and secondary necrosis have been considered the major source of autoantigens and endogenous adjuvants in the pathogenic model of systemic autoimmune diseases. This focus is justified in part because initial evidence in systemic lupus erythematosus (SLE) guided investigators toward the study of apoptosis, but also because other forms of cell death were unknown. To date, it is known that many other forms of cell death occur, and that they vary in their capacity to stimulate as well as inhibit the immune system. Among these, NETosis (an antimicrobial form of death in neutrophils in which nuclear material is extruded from the cell forming extracellular traps), is gaining major interest as a process that may trigger some of the immune features found in SLE, granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) and Felty’s syndrome. Although there have been volumes of very compelling studies published on the role of cell death in autoimmunity, no unifying theory has been adopted nor have any successful therapeutics been developed based on this important pathway. The recent inclusion of NETosis into the pathogenic model of autoimmune diseases certainly adds novel insights into this paradigm, but also reveals a previously unappreciated level of complexity and raises many new questions. This review discusses the role of cell death in systemic autoimmune diseases with a focus on apoptosis and NETosis, highlights the current short comings in our understanding of the vast complexity of cell death, and considers the potential shift in the cell death paradigm in autoimmunity. Understanding this complexity is critical in order to develop tools to clearly define the death pathways that are active in systemic autoimmune diseases, identify drivers of disease propagation, and develop novel therapeutics.

Autoimmune Diabetes: Caught in a NET

“…But such NETs are also potentially toxic as they can activate other innate effector cells to release inflammatory cytokines, promoting NET formation and exposing the immune response to cellular antigens in a feed-forward inflammatory loop, as shown in systemic lupus erythematosus (20). As potential autoantigens exposed by NETs can undergo enzymatic posttranslational modification, this process, controversially called NETosis as it is not certain that the neutrophils are dead, could be important in promoting loss of selftolerance and autoimmunity (20) (Fig. 1).…”

La pêche miraculeuse des filets du neutrophile

“…Les NET exposent dans l'espace extracellulaire de nombreux auto-antigènes potentiels, comme l'ADN double brin ou la myéloperoxy-dase (MPO). Ainsi, 74 % des protéines présentes sur les NET ont été identifiées comme des autoantigènes caractéristiques de différentes maladies auto-immunes systé-miques, comme le lupus, la polyarthrite rhumatoïde (PR) et les vascularites [13]. Une dérégulation de la nétose (par excès de production ou défaut de dégradation) pourrait augmenter le risque d'auto-réactivité vis-à-vis des composants des NET.…”

“…De nombreuses études ont montré, dans les modèles animaux, que le démantèlement des fibres d'ADN des NET par des DNases exogènes exerçait un effet protecteur au cours de diverses situations pathologiques associées à un excès de NET [29,34,35]. La DNase est la seule molécule ciblant les NET qui fasse déjà l'objet d'une utilisation en clinique, puisque l'inhalation de DNase recombinante fait partie de l'arsenal thérapeu-tique de la mucoviscidose, permettant d'améliorer les fonctions pulmonaires et de réduire les exacerbations infectieuses [13]. L'administration de DNase couplée à la neutralisation des histones (par l'emploi d'anticorps spécifiques ou d'acide polysialique, par exemple) ou à celle des protéases constitue donc une piste intéressante contre les effets délétères des NET [12].…”

Cathelicidin – Its Structure, Function and the Role in Autoimmune Diseases

“…Therefore, it concurrently exposes immunostimulatory molecules, activates plasmacytoid dendritic cells (pDC) to produce INF-α, acts toxically on epithelium, participates in the antibody production and complement activation, as well as has its role in the organ damage [4,5,13,24,26,52]. Furthermore, citrullinated histones impair endothelial cells [17] and contribute to the development of new autoantigens [9] activated by NET protein exposure, due to the DNase inhibitors protecting the DNA against degradation [26]. This DNA degradation inhibition results from the LL-37 protective function and the high level of antibodies against the NET components, or its binding with C1q [53].…”

“…AMPs were divided into three groups, which reflects their structure, characteristics, as well as their scope and mode of action [2,9,48]:…”