06 Apr The Intriguing Role of Macrophages in Rheumatoid Arthritis
Key players in the body’s defenses, macrophages are immune cells that swallow bacteria, viruses or infectious germs. When the body comes under attack, these white blood cells engulf the attackers and eliminate the threat. Like characters in a Pac-Man video game, they roam the body, chasing and digesting invaders.
Macrophages play a critical role in both health and disease. With funding from the Arthritis National Research Foundation, The Winter Lab of Functional Genomics is studying the role of macrophages in chronic inflammatory diseases like rheumatoid arthritis (RA).
“Macrophages arise in the bone marrow as precursor cells called monocytes,” explains Deborah R. Winter, PhD, an Assistant Professor in the Division of Rheumatology at Northwestern University Feinberg School of Medicine. “When the immune system works normally, those circulating monocytes transform into macrophages that swallow the invaders. In RA, macrophages that are supposed to disappear can linger and inflame the joints. The healthy macrophages that are supposed to be there can’t compete.”
How does rheumatoid arthritis differ from premature aging?
The immune system declines with age, destroying the body’s ability to combat infection or other threats. Scientists want to know whether the same processes that drive aging and also drive rheumatoid arthritis. As people age, stem cells in the bone marrow spur the overproduction of monocytes that lead to chronic inflammation.
“We found that the monocytes were a problem even before they became macrophages,” says Dr. Winter. “In mice that are genetically engineered to be born with RA-like disease, the monocytes are predisposed to become inflamed. These cells enter the bloodstream and go straight to the joints. The result is the painful joint swelling, stiffness and pain of rheumatoid arthritis.”
At first, Dr. Winter expected that both aging and RA would share similar inflammatory pathways. To her surprise, the mouse models showed that RA differs from premature aging in significant ways. While aging mice had a larger number of monocytes in the blood, in arthritic mice, monocytes were funneled directly to the joints.
What are the key genomic factors that drive macrophages away from their normal healthy function?
As research breakthroughs continue to bring new hope for people with rheumatoid arthritis, scientists are looking deep into the genome to understand why macrophages go awry in RA. In her lab, Dr. Winter is using the power of genomics to explore how macrophages promote chronic inflammatory diseases.
“I truly believe that genomic approaches, such as mine, hold the key to fully understanding the development of RA and similar diseases,” she says. “Once we understand how RA happens, we will be much better placed to develop effective treatments.”
Using a variety of techniques — from crunching “big data” to next-generation sequencing — Dr. Winter is investigating how genes are regulated and expressed. She is exploring gene regulatory networks that define the development of different cells in the immune system.
“We want to understand how cells respond at the genomic level,” Dr. Winter says. “We spend a lot of time collecting data, but the fun part is analyzing our results. The next step is to use high-throughput sequencing to discover the underlying mechanisms controlling which genes are being expressed.”
Dr. Winter is using her background in computational biology and immunology to decipher complex patterns of gene expression. Although macrophages are widespread throughout the body, the body programs them for specific functions, such as pruning synapses in the brain or recycling red blood cells in the liver.
Her findings suggest blocking the production of macrophages that boost joint inflammation could slow or prevent RA. “Currently available treatments decrease inflammatory substances throughout the entire body,” she says, “but these drugs also compromise the body’s ability to respond to infection. Instead of taking a hammer to the whole body, we want to find a way to hit the nail safely on the head.”
Thanks to the Arthritis National Research Foundation, she was able to establish an independent lab. “This award was a big jump for a junior researcher in her first position as an investigator,” says Dr. Winter. “I am bringing my unique perspective to understanding how macrophages malfunction in RA. Genomic approaches offer really exciting potential targets for individuals who are suffering from this devastating disease.”