A master switch protein found in some white blood cells is key in suppressing or promoting inflammation, researchers from Imperial College, London, wrote in the journal Nature Immunology. They added that their findings could eventually lead to new therapies for rheumatoid arthritis and other chronic autoimmune diseases.
When there is tissue damage or an infection, the body has a protective inflammatory response. However, in some cases there is so much inflammation that it can be harmful. In rheumatoid arthritis for example, the joints swell up and become extremely painful. Scientists have been uncertain why this occurs.
Macrophages, types of white blood cells that gobble up foreign materials, are key players in the immune response to foreign invaders, such as infectious microorganisms. Macrophages release chemical signals that can alter the behavior of other cells, triggering inflammation or suppressing it.
The researchers demonstrated in this latest study that IRF5, a protein, acts as a molecular switch, effectively controlling whether macrophages trigger or suppress inflammation.
Many autoimmune diseases, such as rheumatoid arthritis, lupus, inflammatory bowel disease, and MS (multiple sclerosis) might respond well by blocking IRF5 production in macrophages. Conversely, some immune-suppressed patients may need to enhance their immune systems - raising levels of IRF5 might help them.
The scientists had previously developed anti-TNF treatments, using a type of drug commonly used for rheumatoid arthritis. The medications target TNF, a signaling chemical that immune cells release to promote an inflammatory response. The problem is that about one third of patients do not respond to anti-TNF drugs.
Senior researcher, Dr Irina Udalova, said:
"Diseases can affect which genes are switched on and off in particular types of cells. Understanding how this switching is regulated is crucial for designing targeted strategies to suppress unwanted cell responses.
"Our results show that IRF5 is the master switch in a key set of immune cells, which determines the profile of genes that get turned on in those cells. This is really exciting because it means that if we can design molecules that interfere with IRF5 function, it could give us new anti-inflammatory treatments for a wide variety of conditions."
Previous gene association research has linked variations in the IRF5-encoding gene with a higher chance of developing autoimmune diseases. Dr Udalova and Mr Thomas Krausgruber (Ph.D. student), set out to determine how the protein influences inflammation.
Genetically-engineered viruses were used to introduce extra copies of the IRF5 gene in (human) macrophages grown in the lab. The aim was to get the cells to produce more IRF5. When this was done on macrophages with anti-inflammatory characteristics, they switched and triggered inflammation.
They were able to get an opposite result by blocking IRF5 in macrophages with pro-inflammatory characteristics. The cells' production of signals that promote inflammation dropped.
They examined genetically-modified mice that could not produce IRF5. The mice were found to produce significantly lower levels of inflammation-stimulating chemical signals.
IRF5 appears to suppress inflammation-inhibiting genes and switches on inflammatory-response genes, the authors reported. This is done by either interacting directly with DNA, or working together with other proteins which control which genes are activated.
The team is currently studying IRF5 at a molecular level to determine how it does this. They are also studying which other proteins IRF5 interacts with so that ways can be devised to halt its effects.
The authors wrote in the Nature Immunology Abstract:
"Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor."
"IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses"
Thomas Krausgruber, Katrina Blazek, Tim Smallie, Saba Alzabin, Helen Lockstone, Natasha Sahgal, Tracy Hussell, Marc Feldmann & Irina A Udalova
Nature Immunology Year published: (2011) DOI: 10.1038/ni.1990
Written by Christian Nordqvist