Can we balance immune responses by regulating metabolism?
Dr. Steven Bensinger and his team made the unexpected finding that immune cells profoundly change their cellular metabolism during immune responses. This discovery helped put a budding area of study—immunometabolism—on the map. Now his lab hopes to find out if targeting immune cells' metabolism presents a novel way to modulate immunity.
Linking Metabolism and Inflammation
When Dr. Bensinger first started exploring immunometabolism, inflammation had long been associated with a variety of metabolic disorders, but no one knew what might drive the association. He decided to find out by examining the problem with an immunologist’s eye and centering his questions around infection.
Observation: Viral infections change the metabolism of a cell because viruses hijack host cells’ metabolism to replicate.
Hypothesis: The immune system knows a metabolic change could indicate a viral infection. Perhaps the immune system sends an infection alert in response to any atypical change in metabolism, even changes caused by diet instead of viruses. The alert triggers an immune attack, leading to acute inflammation.
Steven Bensinger, VMD, PhD
Director, Immunity, Inflammation, Infection & Transplantation (I3T) Research Initiative
Associate Professor, Microbiology, Immunology & Molecular Genetics
Test: The team manipulated cell metabolism to see how metabolic processes influence immune responses in the absence of infectious agents.
Result: Cells with manipulated metabolisms release molecules that cause inflammation.
Conclusion: In the absence of pathogens, simply manipulating the metabolism of a cell causes inflammation.
Translating the Discovery to Improve Human Health
To translate the link between the immune system and metabolism into meaningful insight for human health, Dr. Bensinger set out to define the molecular process through which metabolic changes lead to inflammation.
By tracing these systemic mechanisms in the lab, the team hopes to selectively modulate the pathways, restoring immune system homeostasis and achieving optimal human health. For example, physicians could turn up inflammation to prompt a stronger immune response to cancer or even turn down inflammation to combat autoimmunity.
The Bensinger Lab uses advanced instruments and analytical approaches to study the interplay of inflammation and metabolism in real time. The team measures metabolites, observes fatty acid synthesis, and studies the signals, proteins, and genes driving a range of processes.
Through strategic observation and analysis, the team has already outlined some critical pages in the immunometabolism playbook.
- Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling. Read more in Cell.
- Modulation of PICALM levels perturbs cellular cholesterol homeostasis. Read more in PLOS One.
- Resetting lipid metabolism restores T cell function in systemic lupus erythematosus. Read more in the Journal of Clinical Investigation.
The Future of Immunometabolism
The Bensinger Lab is one of the only labs in the world studying inflammation and metabolism. The researchers believe their work will reveal novel possibilities in selective immune modulation, a capability that could define the future of medicine.
Dr. Bensinger chairs a research initiative aiming to harness the immune system and transform health. The Immunity, Inflammation, Infection, and Transplantation (I3T) Unified Research Theme unites scientists across campus studying vastly different diseases that are all rooted in the same immune processes. The group hopes a consolidated research infrastructure and intellectual synergy will lead to significant progress in everything from brain cancer to infection.
The immune system has expressed remarkable elasticity throughout the history of human disease. For example, lymph nodes swell and shrink as infections come and go.
We know the immune system can turn itself up or down. Dr. Bensinger wants to find out if we, too, can regulate it.