The Crosstalk Between NETs and the Complement Cascade: An Overview in Nephrological Autoimmune Disease

Abstract

The complement cascade and Neutrophil Extracellular Traps (NETs) represent fundamental tools in protecting the host from foreign pathogens. Complement components and relative fragments, classically assigned to the innate immunity, represent a key link with the humoral immune response. NETs are a crucial component of the innate immune response, consisting of chromatin release from activated neutrophils. These web-like structures facilitate pathogen entrapment and elimination through proteolytic degradation and antimicrobial effectors. Previous findings suggested complement components and NETs have a significant role in the pathogenesis of several diseases characterized by inflammation, such as autoimmune and infectious diseases. However, the crosstalk between NETs and the complement cascade has only recently been investigated, and several aspects still need to be fully clarified. Recent evidence seems to suggest a bidirectional link between the complement cascade and NETosis. We here present the interaction between complement components and NETs in specific autoimmune diseases that mostly affect the kidney, such as systemic lupus erythematosus, Antineutrophilic Cytoplasmic Antibody (ANCA)-associated vasculitis and antiphospholipid syndrome. The mechanisms reported here may represent specific targets for the development of possible therapeutic strategies.

Keywords: ANCA vasculitis; Neutrophil Extracellular Traps; Systemic Lupus Erythematosus; antiphospholipid syndrome; autoimmunity; avacopan; complement cascade; eculizumab.

Figure 1

Representative inflammatory mechanisms leading to NETosis. Neutrophils are activated by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) through binding with Toll-like receptor (TLR) or IgG-Fc receptors, with consequent release of Ca²⁺ by the ER. The cytoplasmic increase of Ca²⁺ activates the protein Kinase-C (PKC) through the RAF–MEK–MAPK/ERK pathway, a critical intracellular signaling pathway that regulates cell proliferation, differentiation, survival, and apoptosis. Ca²⁺ influx and PKC activation have pivotal roles in stimulating NADPH oxidase activity on the cell surface, promoting the production of reactive oxygen species (ROSs). The increase in ROSs induces the release of enzymes such as neutrophil elastase (NE) and myeloperoxidase (MPO). These, together with peptidyl arginine deiminase 4 (PAD4) are commonly localized in the nucleus and involved in chromatin decondensation. The NET produced from neutrophils is therefore composed of DNA, histones, other nuclear components, and intracellular enzymes such as NE and MPO.

Figure 2

Main mechanisms of interplay between complement cascade and neutrophil extracellular traps (NETs). (a) The binding between complement receptors 1 (CR1) and 3 (CR3) on neutrophils with a C3b-opsoninized pathogen commonly leads to phagocytosis and NETosis. Factor H, on neutrophil membranes, limits the inflammatory response, acting as an inhibitor of the link between C3b and CR3. Neutrophils commonly express Factor B and Properdin, which are fundamental for the formation and stabilization of C3-convertase, with consequent activation of the complement cascade. (b) This occurs both at the membrane level and on the NETs. C3b binding to stabilized C3-convertase (1) leads to the formation of C5-convertase (2), which converts C5 into C5a and C5b (3). C5b with C6, C7 and C8 forms the membrane attack complex (MAC) complex (4). Myeloperoxidase (MPO) and cathepsin G, in NETs, can respectively cleave C5 and C3.