Role of Neutrophils in Systemic Vasculitides

Abstract

Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, playing a key role in driving the autoimmune response, the role of neutrophils and NETs in large vessel vasculitis, including giant cell arteritis (GCA), is not well understood. In this review, we summarize the current insight into molecular mechanisms contributing to neutrophil-mediated pathology in small and medium vessel vasculitis, as well as provide potential translational perspectives on how neutrophils, and NETs, may partake in large vessel vasculitis, a rare disease entity of unclear pathogenesis.

Keywords: Behcet’s disease; Takayasu’s arteritis; anti-neutrophil cytoplasmic antibody associated vasculitis; giant cell arteritis; neutrophil extracellular traps; polyarteritis nodosa.

Figure 1

Potential pathogenic mechanisms of NET formation in ANCA-associated vasculitis (AAV) and large vessel vasculitis (LVV). (A) AAV: Pro-inflammatory stimuli such as TNF-α, LPS and C5a cause neutrophil priming, with increased expression of the antigens MPO, PR3, and other neutrophil granule proteins to the cell surface where ANCA can bind to them. Soluble and cell-bound immune complexes of ANCA and ANCA antigens then bind and crosslink FcgRIIA on the neutrophil surface, activating the oxidative burst machinery and driving degranulation of MPO, NE, and PR3, decondensation and extrusion of nucleosomal chromatin from the cells leading to NET formation and eventually neutrophil death. This in turn drives a necrotizing inflammation that results in endothelial cell death, vascular leakage, fibrin deposition, and a subsequent monocyte and macrophage recruitment. This phase eventually evolves into a fibrin and collagen-rich lesion, which may resolve if the initial inflammation was limited, or become permanent scar tissue with lingering chronic mononuclear cell infiltrates with B and T cells in ectopic germinal center-like structures. In these instances, the inflamed artery may be permanently occluded. (B) LVV: We hypothesize that IL-23 that is excreted by the macrophages in the vessel wall induces Th17 cells. Th17 cells then produce IL-17 that up-regulates G-CSF leading to neutrophil recruitment in circulation, and activation of neutrophils. We hypothesize that the presence of ANCA antibodies of unknown entity, may induce neutrophil activation. Alternatively, ANCA antibodies may bind to NETs and form anti-NET antibodies preventing NET degradation as well as creating neutrophil-activating immune complexes. Activated neutrophils then adhere to the endothelium of the affected arteries. Subsequently, neutrophils interact with the damaged endothelium and undergo cell death characterized by NET formation. Endothelial damage perpetuates neutrophil activation via alternative complement activation in a vicious circle. Additionally, we hypothesize that release of mitochondrial components during NET formation leads to formation of anti-mitochondrial antibodies, contributing to vessel wall damage and inflammation.

Figure 2

NET formation in CLAAs. (A) Immunofluorescence microscopy (IF) illustrating levamisole-induced NET formation. Staining was for DNA (blue) and neutrophil elastase (NE, red). (B) IF demonstrating CLAAS IgG binding to cytosolic components, as well as NET-derived antigens. Staining was for DNA (green) and CLAAS IgG (red). Those are alternative images prepared according to the methods outlined in ref (72).