Overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases

By Bhavana KunkalikarReviewed by Benedette Cuffari, M.Sc.Oct 23 2022

In a recent Nature Reviews Immunology journal study, researchers assess the role of neutrophil extracellular traps (NETs) in systemic autoimmune and autoinflammatory disorders.

Study: Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases. Image Credit: Luca9257 / Shutterstock.com

Background

Recent research has shown that neutrophils, particularly NETs released upon activation, have critical roles in the onset and progression of systemic autoimmune disorders and in the development of complex inflammatory responses that cause organ damage.

Autoantigens can be altered and presented to the adaptive immune system due to dysregulated neutrophil cell death. The intricacy of neutrophil biology and its dysregulation can now be better understood as a result of novel technologies that enable better assessments of neutrophils.

NETs in systemic autoimmune diseases

In systemic autoimmune diseases, the immune system cannot distinguish between self and non-self and subsequently responds to and harms several tissues and organs, including joints, kidneys, and blood vessels.

Numerous studies have linked neutrophils to the pathogenesis of systemic autoimmunity. In both human and animal disease models, these immune cells are frequently located at the areas of tissue inflammation where they support inflammatory response.

In particular, the formation of NETs has attracted attention due to their association with autoimmunity. Many of the autoantigens generated by neutrophils in NETs, including double-stranded deoxyribonucleic acid (DNA), citrullinated peptides, histones, myeloperoxidase (MPO), and proteinase 3 (PRTN3), are known to be attacked by the adaptive immune system observed in systemic autoimmunity.

Systemic lupus erythematosus (SLE)

SLE is a type I interferon response-heavy systemic autoimmune disease that displays high autoreactivity against nucleic acids and other nuclear and intracellular components. The skin, synovial joints, kidneys, lungs, blood vessels, and heart are some of the many organs affected by this broad inflammation, making it the classic systemic autoimmune disorder.

As the condition worsens, neutrophil-specific gene expression is enriched in the neutrophil populations of SLE patients relative to healthy controls. In addition, neutrophils from people with SLE have aberrant oxidative metabolism, increased apoptosis, and decreased phagocytic clearance.

Compared to NETs made from neutrophils with normal density, low-density granulocytes (LDGs) from individuals with SLE show a higher propensity to produce NETs ex vivo. They have higher concentrations of modified autoantigens and immunostimulatory molecules.

Rheumatoid arthritis

As the most common systemic autoimmune illness, rheumatoid arthritis causes a heavy strain on both the patient and society. In addition to frequently affecting extra-articular tissues like the lungs and vasculature, this condition specifically targets the synovial joints, which, if not adequately treated, can result in considerable disability.

Since neutrophils produce enzymes like peptidylarginine deiminase 4 (PAD4) that catalyze the conversion of arginine to citrulline, they are a key source of citrullinated antigens. Particularly in the initial phases of the disease, rheumatoid arthritis patients have an abundance of neutrophils in their inflamed joints that might produce NETs locally.

Patients with rheumatoid arthritis have elevated amounts of NETs in their blood, which are correlated with levels of anti-citrullinated protein antibodies (ACPAs) and other systemic inflammatory markers.

Neutrophils in systemic autoinflammation

Inflammatory responses primarily involve innate immune cells, such as neutrophils, which are the leading cause of autoinflammatory disorders. Recent studies suggest that accurately distinguishing between autoinflammation and autoimmunity can be challenging. Instead of two separate events, these processes can be the extremes of an inflammatory spectrum.

Adenosine deaminase 2 deficiency

Adenosine deaminase 2 (ADA2) is a protein responsible for the breakdown of extracellular adenosine and is primarily expressed by myeloid cells. Adenosine deaminase deficiency (DADA2) is characterized by monogenic vasculitis driven by a biallelic mutation in the ADA2 gene.

DADA2 has a diverse range of clinical manifestations, including vasculitis and autoinflammation. In addition, as a result of the ADA2 mutation's lower protein activity, extracellular adenosine levels rise, which can cause NETs to develop by binding to neutrophil A1 and A3 adenosine receptors.

People suffering from DADA2 also have higher levels of circulating LDGs, which can form NETs. Compared to NETs obtained from healthy controls, these NETs cause macrophages to create more inflammatory chemicals, such as tumor necrosis factor (TNF), which may be due to variations in NET molecular composition.

PAPA syndrome

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome can manifest in several ways, including arthritis involving the sterile joint buildup of neutrophils. This condition is commonly diagnosed in children.

Several studies have noted increased NET production and reduced NET clearance in neutrophils from PAPA syndrome patients. Additionally, compared to neutrophil levels in healthy controls, neutrophils in PAPA syndrome patients respond more robustly to interleukin 1(IL-1). Incubating these neutrophils with anakinra, an IL-1 receptor antagonist, can suppress NET formation.

NET remnants that have infiltrated the skin and are linked to inflammatory cytokines and increased neutrophil transcriptional responses have been found in skin biopsies from PAPA syndrome patients. Overall, a connection between IL-1 with dysregulated neutrophil responses in the PAPA syndrome pathogenesis has been reported.

Conclusions

The current study reports that neutrophils have a significant function in various inflammatory diseases. By targeting tissues to foster an inflammatory environment and produce neoepitopes, neutrophils play crucial roles in the onset and progression of autoimmune diseases.