Neutrophil extracellular traps (NET): not only antimicrobial but also modulators of innate and adaptive immunities in inflammatory autoimmune diseases

Abstract

Polymorphonuclear neutrophils (PMN) represent one of the first lines of defence against invading pathogens and are the most abundant leucocytes in the circulation. Generally described as pro-inflammatory cells, recent data suggest that PMN also have immunomodulatory capacities. In response to certain stimuli, activated PMN expel neutrophil extracellular traps (NET), structures made of DNA and associated proteins. Although originally described as an innate immune mechanism fighting bacterial infection, NET formation (or probably rather an excess of NET together with impaired clearance of NET) may be deleterious. Indeed, NET have been implicated in the development of several inflammatory and autoimmune diseases as rheumatoid arthritis or systemic lupus erythematosus, as well as fibrosis or cancer. They have been suggested as a source of (neo)autoantigens or regulatory proteins like proteases or to act as a physical barrier. Different mechanisms of NET formation have been described, leading to PMN death or not, depending on the stimulus. Interestingly, NET may be both pro-inflammatory and anti-inflammatory and this probably partly depends on the mechanism, and thus the stimuli, triggering NET formation. Within this review, we will describe the pro-inflammatory and anti-inflammatory activities of NET and especially how NET may modulate immune responses.

Keywords: Arthritis; Autoimmunity; Inflammation; Lupus Erythematosus; Rheumatoid; Systemic.

Figure 1

Direct effects of NET on myeloid cells. Direct interaction of NET with different cell types and its consequences in the absence (blue arrows, lower part) or presence (black arrows, upper part) of LPS. Effects of NET-containing immune complexes are not depicted. Data are pooled from human studies, both in healthy individuals and patients with inflammatory autoimmune diseases. Mechanisms highlighted as stronger in patients as compared with healthy individuals refer to data with either NET from patients or target cells from patients. HI, healthy individuals; IFN-I, type I interferon; LPS, lipopolysaccharides; mDC, myeloid dendritic cells; MΦ, macrophages; NET, neutrophil extracellular traps; PMN, polymorphonuclear neutrophils; pre-MΦ, macrophages obtained after only 3 day differentiation; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.

Figure 2

Direct and indirect effects of NET on B and T lymphocytes. (A) NET effects in a physiological context. On the left part (red arrows), NET inhibit myeloid DC activation in response to LPS, leading to impaired T-cell response. On the right panel (green arrows), NET directly activate memory B lymphocytes to secrete total IgG. NET can also prime resting CD4⁺ T cells, leading to CD25 and CD69 upregulation, as well as ZAP70 phosphorylation, without requiring dendritic cells. Likewise, NET stimulate resting DC to activate resting CD4⁺ T cells, favouring a Th1-like response. Data are pooled from studies with NET and target cells from healthy individuals. (B) NET effects in a pathological context. In type 1 diabetes (green background), NET stimulate myeloid dendritic cells to activate Th1 lymphocytes. In SLE (pink background), NET directly activate memory B lymphocytes to secrete ANCA. Finally, in RA (blue background), NET activate fibroblast-like synoviocytes on internalisation and NET peptides are presented to antigen-specific CD4⁺ T cells, leading to their activation. NET also activate myeloid dendritic cells, which potentially (dotted line) stimulate T lymphocytes. Effects of NET-containing immune complexes are not depicted in this figure. ANCA, anti-neutrophil cytoplasmic antibodies; DC, dendritic cells; FLS, fibroblast-like synoviocytes; LPS, lipopolysaccharides; mDC, myeloid DC; NET, neutrophil extracellular traps; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.