The Role of NETosis in Systemic Lupus Erythematosus

Abstract

BackgroundSystemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that affects women to men at a ratio of 9:1 and is predominant in those of African ancestry. In SLE, the presence of autoantigens results in aberrant immune activation leading to systemic inflammation that predominantly affects the brain, kidneys, blood, and skin. Current guidelines recommend treatment with immunosuppressive drugs like prednisone, cyclophosphamide, azathioprine, and even some antimalarial drugs [1,2]. However, such drugs have limited efficacy, and result in toxic side effects. Therefore, research into the mechanism of the pathogenesis of SLE in order to identify novel therapies is important.Autoantibodies generated in SLE induce influx of neutrophils to different sites of the body. Neutrophils are the body's first line of defense against pathogens and are the most abundant leukocytes in the blood stream. The normal percentage of neutrophils (50%) can increase to 80% on site of a bacterial infection and detection of tissue inflammation. Neutrophils utilize various mechanisms of defense including phagocytosis, nicotinamide adenine dinucleotide phosphate (NADPH) oxidative burst, as well as the release of reactive oxidative species (ROS) and enzymes. More recently, it was discovered that dying neutrophils release 'spider web' like chromatin fibers called neutrophil extracellular traps (NETs). The release of NETs by activated neutrophils is known as NETosis [3]. These NETs are constructed of decondensed chromatin, histones, granules, and components with bactericidal activity. Antimicrobial enzymes such as myeloperoxidase (MPO), neutrophil elastase (NE), cathelicidins like LL-37, histones, proteinase 3, cathepsin, lactoferrin, or gelatinase are expelled with NETs, enabling them to entrap, inhibit, and kill invading pathogens in an extracellular manner, rather than the canonical method of phagocytosis [3,4].

Effect of add-on hydroxychloroquine therapy on serum proinflammatory cytokine levels in patients with systemic lupus erythematosus

“…We previously reported that HCQ modulates the serum levels of S100A8 and S100A9, which are associated with disease activity in SLE patients with LDA 30 . S100 proteins are components of neutrophil extracellular traps (NETs) 31 , which play an important role in the pathogenesis of SLE 32 – 34 . In addition, chloroquine and HCQ are reported to inhibit NETs in vivo and in vitro 35 – 37 , suggesting the involvement of S100 protein regulation in their underlying mechanism of action.…”

The emerging role of neutrophils in autoimmune‐associated disorders: effector, predictor, and therapeutic targets

“… 51 Neutrophil dysregulation is related to SLE's pathogenesis, abnormal neutrophils fueling inflammatory states by producing disease‐inducing cytokines (IL‐1β or BLyS) and becoming a source of many autoantigens in the disease through NETosis. 52 …”

Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis

“…As a disease tempering role, they catch pro-inflammatory cytokines and proteolytically degrade them to resolve the inflammation (171). In contrast, NETs are also highly immunogenic and were linked to the development of several autoimmune diseases including RA and systemic lupus erythematosus (SLE) (172)(173)(174)(175)(176)(177)(178)(179)(180). In sJIA patients, NETosis was never directly studied ex vivo.…”