Neutrophils and Platelets as Key Players in the Pathogenesis of ANCA-Associated Vasculitis and Potential Sources of Disease Activity Biomarkers

Abstract

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a heterogeneous group of small-vessel vasculitides, characterized by the presence of antibodies binding to myeloperoxidase (MPO) and proteinase-3 (PR3) found in neutrophil granules. Apart from being the target of ANCA, neutrophils actively contribute to the vicious cycle of inflammation and vascular damage in AAV. On the other hand, platelets have recently been recognized as essential for thrombosis and as inflammatory effectors that collaborate with neutrophils, reinforcing the generation of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in those diseases. Neutrophils exhibit morphological and functional heterogeneity in AAV, reflecting the complexity of their contribution to disease pathogenesis. Since long-term immunosuppression may be related to serious infections and malignancies, there is an urgent need for reliable biomarkers of disease activity to optimize the management of AAV. This review summarizes the current understanding of the role of neutrophils and platelets in the pathogenesis of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), focusing on their crosstalk, and highlights the potential for identifying novel biomarkers relevant for predicting the disease course and its relapses.

Keywords: ANCA-associated vasculitis (AAV); biomarkers; extracellular vesicles (EVs); myeloperoxidase (MPO); neutrophil extracellular traps (NETs); neutrophils; platelets; proteinase-3 (PR3).

Figure 1

Neutrophil adhesion cascade preceding extravasation. This process involves capture, rolling, activation, firm adhesion, and intraluminal crawling. It depends on interactions of neutrophil glycoproteins with endothelial E- and P-selectins, whose expression is upregulated in inflammatory loci. Firstly, E- and P-selectin capture circulating neutrophils to the surface of endothelium by interacting with E-selectin ligand-1 (ESL-1) and P-selectin glycoprotein ligand 1 (PSGL1), respectively. The interaction of β₂ integrins, namely lymphocyte function-associated antigen-1 (LFA-1, α_Lβ₂, CD11a/CD18) and macrophage-1 antigen (Mac-1, α_Mβ_2, CD11b/CD18) with ligands such as vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule-1 (ICAM-1, CD54), and ICAM-2 on endothelial cells, ensures firm adhesion of neutrophils.

Figure 2

Reactive oxygen species (ROS) play a critical role in AAV. In addition to direct endothelial damage and perpetuating the inflammation via cytokine release, ROS generation is crucial for initiating NETosis. Monocytes and macrophages stimulated by ANCA, ROS, and inflammatory mediatiors release soluble CD163, which urine levels are a relatively novel biomarker of kidney vasculitis flare [83].

Figure 3

Platelet-neutrophil surface interactions in AAV. Upon activation, platelets express adhesion molecules and release inflammatory mediators that engage corresponding receptors on neutrophils. Notable interactions include P-selectin binding to PSGL-1 and platelet-derived HMGB1 engaging RAGE and TLRs on neutrophils, amplifying the inflammatory response through signaling pathways such as NF-κB and MAPK. Additionally, neutrophil MAC-1 interacts with platelet GPIIb/IIIa, facilitating firm adhesion. Leukotriene B4 (LTB4) and its receptors BLT1/2 contribute to neutrophil recruitment and activation.