Diverse Roles of NETosis in the Pathogenesis of Lupus

Abstract

NETosis is a form of neutrophil cell death during which extracellular fibrillary structures composed of cytosolic and granule proteins assembled on scaffolds of decondensed chromatin, called neutrophil extracellular traps (NETs), are released. NETs normally contribute to host immune defense. Accumulating evidence implicates aberrant NET production and/or reduced NET clearance, along with alterations of molecules involved in NETosis pathway, in humans and animals with lupus. The extruded nuclear antigens released by NET are a source of autoantigens, which can contribute to the breakdown of self-tolerance in lupus. Excessive NET can also promote the production of pro-inflammatory cytokine interferon-α, elicit direct cytotoxic effect on various renal cells, and cause capillary necrosis and podocyte loss. Additionally, NET can induce endothelial-to-mesenchymal transdifferentiation, which can promote activated myofibroblasts leading to extracellular matrix production. Thus, aberrant NETosis can play diverse roles, including autoantibody production, inflammation, and tissue damage, at different stages of lupus pathogenesis. Evidence suggests that treatments currently used in lupus may reduce NETosis, suggesting a potential utility of targeting NETosis to treat lupus. In fact, several approaches are being experimented to therapeutically target pathways of NETosis. Future studies should precisely delineate distinct roles of NETosis at different stages of lupus pathogenesis in humans, which would offer a rational basis for NETosis-targeting treatments in the clinic.

The role of NETosis in the pathogenesis of immunoinflammatory rheumatic diseases

“…Патогенетические механизмы, определяющие роль нетоза в развитии ИВРЗ [6,7,[28][29][30][31][32], суммированы в таблице 3.…”

Human neutrophils ≠ murine neutrophils: Does it matter?

“…In some settings, neutrophils, as well as other cells, release extracellular traps (aka ETs), whose DNA may entrap microbes, contribute to autoimmune disease, or promote further inflammation. 27,28 In summary, human neutrophils play a prominent role in every stage of the inflammatory response, as first responders to many different types of threats, as sources of some of the secreted immunomodulators released at the site, and as active participants in the termination of inflammation and the tissue repair needed to restore homeostasis. 29…”

“…Sometimes, as with interactions with particular bacteria, such as Staphylococcus aureus , or when stimulation is excessive, neutrophils undergo a necrotic cell death 24,26 and thereby release cytoplasmic contents that provide danger signals to drive additional inflammation. In some settings, neutrophils, as well as other cells, release extracellular traps (aka ETs), whose DNA may entrap microbes, contribute to autoimmune disease, or promote further inflammation 27,28 …”

EARLY NEUTROPHIL ACTIVATION AND NETs RELEASE IN THE PRISTANE-INDUCED LUPUS MICE MODEL

“…Notably, CD11b expression increases after neutrophils activation [5]. Both qualitative and quantitative alterations are observed in neutrophils from patients with autoimmune diseases as SLE [5,10,[12][13][14]. These alterations include increased number of activated neutrophils [9], reduced phagocytosis capacity with lesser removal of apoptotic material [15][16][17], increased release of neutrophil extracellular traps (NETs), and increased number of low-density granulocytes (LDGs) [18][19][20][21].…”