THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Researchers continue to uncover more RA-related metabolic processes

Inflammation can be a more pernicious process than previously realized. Macrophages and dendritic cells are the front line in immunity, but pro-inflammatory stimuli can shift their entire metabolism toward glycolysis and away from oxidative phosphorylation. The altered metabolic pathways can drive cytokine production to produce damage in joints and possibly other tissues.

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Luke O’Neill, PhD

“Metabolites are being implicated in inflammatory events in the joints,” said Luke O’Neill, PhD, Professor and Chair of Biochemistry at Trinity College Dublin, Ireland. “In a nutshell, we are uncovering metabolic processes that can drive events like rheumatoid and osteoarthritis.”

Dr. O’Neill will explore the converging worlds of inflammation and metabolism during a State-of-the-Art Lecture on Immuno-Metabolism: Energetics and Inflammation from 7:30 – 8:30 am Monday. The presentation is part of the Basic Science Primary Track, but research has already identified therapeutic targets that could move into the clinic in short order.

The metabolite succinate was one of the early keys to the growing understanding of how inflammation can shift metabolic processes to cause disease. Succinate is critical to the inflammatory response in macrophages. It shifts macrophage metabolism toward glycolysis, which can drive production of interleukin-1 and other inflammatory cytokines. At the same time, succinate changes the behavior of mitochondria, which begin to produce reactive oxygen species that boost production of IL-1β and other pro-inflammatory cytokines. The Krebs cycle, which most cells use to produce energy, is suddenly coupled into the production of inflammatory cytokines.

“The overarching principle of immuno-metabolism is to integrate metabolism with the production of cytokines that can result in disease,” Dr. O’Neill said. “It is an entirely new way to look at cytokine dysregulation as a result of inflammatory changes. We have long known that inflammation can disrupt cytokine regulation and production. Now we are starting to understand how and where it happens and find some really promising targets. There is already significant development in interrupting the activity of key metabolic pathways in inflammation. It is the kind of very directed basic research that could well give rise to new therapies down the line. I wouldn’t put a timeline on it, but there are some very promising new directions that I will be talking about.”

Evolving research now looks beyond obvious targets such as succinate. Many of the enzymes active in glycolysis are also recognized antigens commonly seen in rheumatoid disease. Enolase, widely viewed as an autoantigen involved in rheumatoid arthritis, is one of the key enzymes involved in glycolysis. Immunometabolic changes that favor glycolysis are an obvious area of interest.

Immuno-metabolism isn’t just the promise of new therapeutic targets and new agents. It is the promise of new therapeutic concepts, small molecule oral agents that can replace the large molecule biologics that have become the mainstay of rheumatologic disease treatment.

Biologics have been a tremendous improvement over earlier generations of disease-modifying antirheumatic drugs. But biologics are expensive, administration is complex, and side effects can be worrying. The prospect of more targeted, more patient-friendly regimens is attracting as much interest from biotechnology and pharmaceutical companies as it is from academic researchers.

“The whole area of immuno-metabolism is burgeoning,” Dr. O’Neill said. “The metabolic changes seen in inflamed joints have been known about for decades. It has been known for years that some of the glycolytic enzymes we see in inflamed joints are also autoantigens. We are finally starting to fit these pieces together and understand very precisely how these changes relate to disease pathogenesis.”