Immune cells called monocytes produce a key inflammatory protein called interleukin-1 beta (IL-1β) through an unconventional pathway in patients with systemic lupus erythematosus, commonly referred to as lupus, according to a new study by Weill Cornell Medicine investigators.
The findings, published Oct. 7 in Immunity, could lead to new treatments targeting IL-1β to better manage inflammation in patients who don't respond well to existing therapies.
Lupus is a chronic autoimmune disease in which the body's immune system attacks its own tissues, leading to widespread inflammation that can affect the skin, joints, kidneys and heart. There are 20 to 150 cases per 100,000 people in the United States, according to the medical reference source UptoDate. While a genetic basis can be identified in a fraction of patients, the exact cause remains unclear in most of them. The disease is known, however, to involve overproduction of type I interferons (IFNs) -proteins that help the body fight viruses but can also drive harmful inflammation in autoimmune conditions. Yet some lupus patients fail to fully respond to treatments blocking IFNs, prompting the investigators to look for another culprit.
"Lupus is considered an 'interferonopathy' because almost all patients show elevated interferon activity in their blood and tissues," said senior author Dr. Virginia Pascual, director of the Gale and Ira Drukier Institute for Children's Health and the Ronay Menschel Professor of Pediatrics. "It was surprising to find co-activation of both interferon and IL-1β pathways in lupus monocytes, since these proteins typically negatively regulate each other in immune responses."
The current study builds on previous research from 2021, where first author Simone Caielli, an assistant professor of immunology research in pediatrics at the Drukier Institute, and her team discovered red blood cells retaining mitochondria in up to 60% of pediatric patients with lupus but not in healthy controls or patients with the autoimmune disease juvenile dermatomyositis. Mitochondria are normally degraded during the red blood cells' development and the detection of mitochondrial DNA can trigger an immune response characterized by IFN production.
In the new study, Pascual and Caielli found that monocytes produced not only IFN but also IL-1 β upon internalizing lupus red blood cells containing mitochondria. The researchers used in vitro and ex-vivo assays on blood samples from patients with lupus to identify a surprising mechanism in which IL-1β production ultimately results from interactions between the IFN pathway and the inflammasome, a protein complex which is responsible for the production of IL1b and is normally suppressed by IFN.
Importantly, the study also revealed that IL-1β secretion occurs without cell death, a process normally required for this protein's release, making it an attractive target for new therapies.
"Without causing cell death, lupus monocytes could potentially travel through the body, release IL-1β and survive in inflamed areas, amplifying their harmful effects," Caielli said. "These cells may also transform into cells that activate other components of the immune system, worsening the inflammation."
Looking ahead, the researchers plan to study how these immune pathways behave during lupus flareups and remissions, with the goal of refining treatment strategies. They are also developing diagnostic tools to detect monocytes that produce both IFN and IL-1β, which could help identify patients who would benefit from therapies that block both proteins.
The researchers are hopeful that their findings will not only lead to better treatments for lupus patients but may also apply to other autoimmune diseases with similar inflammatory pathways.
This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, both part of the National Institutes of Health; the Lupus Innovation Award/Lupus Research Alliance; and funds from the Drukier Institute for Children's Health at Weill Cornell Medicine.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profiles for Dr. Virginia Pascual and Dr. Simone Caielli.
Jennifer Long is a freelance writer for Weill Cornell Medicine.
