The role of neutrophils in the pathogenesis of systemic lupus erythematosus

Abstract

Purpose of review: Recent discoveries implicate neutrophils as important regulators of innate and adaptive immunity and in the development of organ damage in systemic autoimmune diseases, including systemic lupus erythematosus (SLE).

Recent findings: Various putative SLE biomarkers are neutrophil-related, including neutrophil granular proteins and histones undergoing post-translational modifications during neutrophil extracellular trap (NET) formation. In the bone marrow, lupus neutrophils can drive B and T cell abnormalities, at least in part, by their enhanced production of type-I interferons, tumor necrosis factor-alpha (TNFα) and the B-cell stimulating factors B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Lupus neutrophils and, in particular, lupus low-density granulocytes (a distinct pathogenic subset) display epigenetic modifications and genomic alterations that may be relevant to their deleterious roles in SLE. Proteins and enzymes externalized by lupus NETs can affect vascular health by inducing endothelial apoptosis and oxidizing lipoproteins. Hampering NET formation through peptidylarginine deiminase inhibitors abrogates lupus phenotype and atherosclerosis in murine studies.

Summary: Recent discoveries support the notion that neutrophils, low-density granulocytes and aberrant NET formation and clearance play important roles in lupus pathogenesis. Future studies should focus on how to selectively target these immunostimulatory pathways in this disease.

FIG. 1:

Neutrophil-mediated pathogenesis in SLE. Bone marrow neutrophils may be potent sources of type I IFN, BAFF and APRIL, which promote B- and T-cell activation. NETosis can be induced by autoantibodies, leading to the release of autoantigens and thus autoantibody production. The oxidative machinery produced by NETs (MPO, NOS and NOX) can lead to CVD-associated HDL oxidation. NET-bound MMP-9 leads to enhanced endothelial cell death. LL-37 in NETs enhances inflammasome activation and pDC stimulation, prompting IL-1-β/IL-18 and IFN production, respectively. Antimalarials and PAD-inhibitors may dampen these neutrophil-mediated cell death and proinflammatory signaling pathways, which otherwise can contribute to SLE pathogenesis. SLE, systemic lupus erythematosus; IFN, interferon; BAFF, B-cell activating factor; APRIL, a proliferation-inducing ligand; NETosis, neutrophil extracellular trap formation; MPO, myeloperoxidase; NOS, nitric oxide synthase; NOX, NADPH oxidase; CVD, cardiovascular disease; HDL, high density lipoprotein; MMP-9, matrix metalloproteinase 9; LL-37, Cathelicidin; pDC, plasmacytoid dendritic cell; IL, interleukin; PAD, peptidylarginine deiminase.