Casting the NET Wide: How Neutrophils Shape Chronic Autoimmune and Inflammatory Diseases

NATALIE HAGEN, NCATS

Known as the 'disease with a thousand faces,' systemic lupus erythematosus is a lifelong autoimmune disease with a wide range of symptoms and signs-fatigue, fever, joint pain, facial rash and skin lesions, shortness of breath, and more. It may develop suddenly or slowly and be mild or severe, with people affected going through periods of flare up and remission of their symptoms. Lupus affects mostly women of childbearing age and causes widespread inflammation, damage to organ systems, and premature cardiovascular disease.

Lupus is thought to be caused by an overactive immune system in which autoantibodies attack a body's own cells, tissues, and organs. Normal antibodies attack antigens produced by foreign substances such as bacteria, viruses, or toxins. Autoantibodies, on the other hand, attack autoantigens produced by the body itself.

Previously, it was believed that white blood cells called lymphocytes were the predominant drivers of this disease. Recent discoveries and technical advances, however, have suggested that neutrophils-another type of white blood cell-may also play an important role in immune dysregulation.

NIH Senior Investigator Mariana Kaplan is exploring how neutrophils wreak havoc on the immune system in lupus and other autoimmune disorders. Her interest in immunology was piqued when, as a medical student at the National Autonomous University of Mexico's School of Medicine (Mexico City), she began seeing patients with lupus. 'The idea that someone's body starts attacking itself rather than the outside environment-I thought that was a really fascinating problem,' said Kaplan, who is chief of the Systemic Autoimmunity Branch in the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is also involved in lupus clinical trials in the NIH Clinical Center.

Kaplan has identified several mechanisms, including a role for neutrophils, associated with the development and prevention of premature atherosclerosis in people with lupus. She presented her research on neutrophils and their role in autoimmunity on June 9, 2021, at the annual G. Burroughs Mider Lecture, which is part of the Wednesday Afternoon Lecture Series (WALS).

Neutrophils undergo a process called NETosis: The neutrophils extrude nuclear material bound to cytoplasmic proteins in a meshwork called neutrophil extracellular traps (NETs) that can then capture and kill pathogens. Kaplan determined that this process also causes the neutrophils to release autoantigens-such as host DNA and histones and other proteins.

A subset of proinflammatory neutrophils from patients with lupus, compared with those from patients without, are more likely to form NETs with a greater potential for developing an immune response. The result is increased inflammation and enhanced vascular damage.

There are also differences in how male and female immune systems work. Females have a stronger immune response than males, which may explain why women tend to react better to vaccines and infections. However, that enhanced immune response also makes females predisposed to inflammatory and autoimmune diseases such as lupus. Kaplan has found that sex hormones modulate neutrophil metabolism: Female neutrophils are significantly more active than male ones and have an enhanced ability to form NETs and respond to inflammatory insults. In one experiment, she showed that when male neutrophils are treated with the female sex hormone estradiol, they acquire the bioenergetic profile and behavior of female neutrophils. This finding could have important implications in the context of why women are more likely to get lupus. (Proc Natl Acad Sci U S A117:16481-16491, 2020)

Current treatments for lupus that suppress numerous immune cells and inflammatory cytokines can have serious side effects. Kaplan's findings have implications for the development of new individualized, sex-specific therapies that target neutrophils. Furthermore, strategies that suppress the aberrant NET formation seen in lupus-without hampering other important antimicrobial functions-could prove a useful approach for autoimmune and chronic inflammatory diseases that involve neutrophil dysregulation.

'While in some patients, lymphocytes may be the main players in lupus, there may be other patients [in whom] neutrophils are playing a very important role,' she said. 'So if you treat these patients the same way, you're probably not going to get the same therapeutic response.'

To watch a videocast of Mariana Kaplan's June 9, 2021, WALS lecture, 'Casting the Net Wide: The Role of Neutrophils in Chronic Diseases,' go to https://videocast.nih.gov/watch=41601.

Natalie Hagen is a postbaccalaureate research fellow in the National Center for Advancing Translational Sciences, where she is performing pharmacokinetics studies of novel drug candidates. Upon completion of her fellowship in 2022, she is planning to pursue a Ph.D. In her spare time, she likes to run, read, and go hiking with friends.

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