Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases

Abstract

Systemic autoimmune diseases are characterized by the failure of the immune system to differentiate self from non-self. These conditions are associated with significant morbidity and mortality, and they can affect many organs and systems, having significant clinical heterogeneity. Recent discoveries have highlighted that neutrophils, and in particular the neutrophil extracellular traps that they can release upon activation, can have central roles in the initiation and perpetuation of systemic autoimmune disorders and orchestrate complex inflammatory responses that lead to organ damage. Dysregulation of neutrophil cell death can lead to the modification of autoantigens and their presentation to the adaptive immune system. Furthermore, subsets of neutrophils that seem to be more prevalent in patients with systemic autoimmune disorders can promote vascular damage and increased oxidative stress. With the emergence of new technologies allowing for improved assessments of neutrophils, the complexity of neutrophil biology and its dysregulation is now starting to be understood. In this Review, we provide an overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases and address putative therapeutic targets that may be explored based on this new knowledge.

Fig. 1. The life cycle and functions of neutrophils.

Mature neutrophils are released from the bone marrow into the circulation. Circadian rhythm regulates the biology of neutrophils, their release from the bone marrow and their migration into tissues, but these processes are also modified by inflammatory conditions that involve an increased systemic demand for neutrophils. Most neutrophils have a short half-life and live for only 1 day or less in the circulation. During this time, the expression of several surface markers increases as neutrophils age, including CD16 (also known as FcγRIII), CD10, CD11b (also known as integrin αM) and the chemokine receptor CXCR4. This allows for the entry of neutrophils into other tissues, such as lung, liver, kidney and skin, where they carry out sentinel functions surveying for invading microorganisms as well as physiological functions, including angiogenesis, coagulation and tissue repair. It is still unclear if these tissue-resident neutrophils represent functional subsets, or if neutrophil subsets, such as low-density granulocytes, can be detected in the circulation. The end of the neutrophil life-cycle involves the bone marrow, liver or spleen, where neutrophils can be phagocytosed and degraded by macrophages. If neutrophils encounter an inflammatory signal, they can exit the circulation by extravasation to reach the site of injury. Neutrophils can respond to microorganisms in several ways, including intracellular degradation (phagocytosis), extracellular degradation (degranulation), and extracellular trapping and degradation (neutrophil extracellular trap (NET) formation).

Fig. 2. Targeting neutrophil extracellular traps.

The formation of neutrophil extracellular traps (NETs) can be triggered by various stimuli through engagement of surface receptors such as cytokine receptors, Fcγ receptors (FcγRs), Toll-like receptors (TLRs), damage-associated molecular pattern (DAMP) receptors, complement receptors (such as C5aR), and A1 or A3 adenosine receptors, which often converge on causing increased intracellular concentrations of Ca²⁺. This leads to the activation of PKC, assembly of the NADPH oxidase machinery and/or mitochondrial activation, leading to the generation of reactive oxygen species (ROS). Eventually, there is fusion of neutrophil granules with the nucleus, activation of the cell cycle proteins CDK4 and CDK6, histone citrullination by peptidylarginine deiminases such as peptidylarginine deiminase 4 (PAD4), and decondensation of the chromatin. The granule protein neutrophil elastase can activate gasdermin D (GSDMD) to form pores in the nuclear and plasma membranes. After degradation of the nuclear membrane and cytoskeletal structures, the chromatin–protein mixture is released into the extracellular space. Under normal conditions, these NET structures are eventually degraded and removed by DNses and macrophages, thus resolving inflammation. The NET process can be targeted by pharmacological interventions at several levels: inhibiting the activation of surface receptors, targeting intracellular processes in the neutrophil, and promoting the removal or neutralization of NET products such as myeloperoxidase (MPO) and neutrophil elastase. COX, cyclooxygenase.

Fig. 3. Organ-specific effects of neutrophils in autoimmune and autoinflammatory diseases.

a | In some autoimmune conditions, such as systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis, glomerulonephritis occurs associated with the deposition of circulating immune complexes in the kidney glomeruli that can promote neutrophil recruitment and aggregation. The resulting complement activation and neutrophil extracellular trap (NET) formation recruit further immune cells and damage renal tissue, which leads to the exposure of additional autoantigens and formation of more immune complexes. b | The vasculature can be affected in most autoimmune conditions in some form, including rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. Circulating immune complexes that contain NET autoantigens coupled with autoantibodies may contribute to vascular inflammation and endothelial dysfunction. NET products can have a direct pathogenic effect on the vessel wall by destroying endothelial cells and smooth muscle cells (SMCs). Activated neutrophils can infiltrate the endothelium, triggering monocytes and macrophages to release cytokines that recruit more immune cells. c | The joints are also a common target in autoimmunity. Neutrophils can attack joint structures promoting pain, inflammation and loss of function. Several molecules released from neutrophils cause modification and subsequent destruction of cartilage and bone, triggering an adaptive immune response against self-targets and promoting the development of autoantibodies. These autoantibodies can form immune complexes in the joint, further activating neutrophils and leading to NET formation. PAD, peptidylarginine deiminase.