Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

Abstract

Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins. Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE). Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies. An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE. Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease. In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition. We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease.

Neutrophils in chronic inflammatory diseases

“…This population is known as low-density neutrophils (LDNs) [ 50 ]. The LDN population was first described in SLE and RA [ 51 ] and has now been well characterized in both diseases [ 52 , 53 ]. The LDN population includes granulocytic/polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) with immunosuppressive properties and low-density granulocytes (LDGs), which are characterized as having proinflammatory effects [ 54 , 55 ].…”

Low Density Neutrophils Are Increased in Patients With Behçet’s Disease but Do 3 Not Explain Differences in Neutrophil Function

“…A recent review discusses further differences between neutrophil phenotype in different disease with energy metabolism and glycolysis driving ROS and NET production in RA, while decreased redox reactions drive the same in SLE. [35] NET formation has an important role in the development and preservation of autoimmune diseases, organ damage in chronic inflammatory disorders and cancer. [36][37][38] In our study total neutrophils, LDN and NDN in patients with BD showed increased production of cfDNA compared with healthy controls when stimulated with PMA or E.coli.…”

Inhibition of NETosis for treatment purposes: friend or foe?

“…Furthermore, anti-histone autoantibodies are also common in these patients [65]. In addition to anti-dsDNA and histone autoantibodies in SLE patients, autoantibodies against other NET components including high-mobilitygroup protein 17 (HMG-17), lamin B1, lamin B2, catalase, cathelicidin (LL37), apolipoprotein A, α-enolase, and annexin AI have been rarely detected [12,66]. It is also noteworthy that NET proteins in SLE patients can contribute to tissue damage.…”

“…Following excessive NET formation and release of autoantigen, plasmacytoid dendritic cells (pDCs) can recognize the exposed autoantigens leading to interferon and autoantibody production, which are accompanied by tissue damage [12]. Therefore, regarding the pathologic role of NET formation, it has been considered more by researchers as an attractive therapeutic target [13].…”

“…In this context, the use of NET inhibitors has been investigated in various studies [14][15][16]. NET can also be indirectly targeted and reserved by inhibition of protein arginine deiminase 4 (PAD4), Myeloperoxidase (MPO), and neutrophilic elastase [12]. Studies in animal models of inflammation as well as human respiratory disorders showed that inhibition of MPO and neutrophilic elastase significantly reduced neutrophil-mediated inflammation [17,18].…”