An investigation of the mechanisms linking MACIR with tissue damage in rheumatoid arthritis

The immune system is often looked upon as a response to infection. While it has this function, it also does so much more, including being crucial for the normal growth and replenishment of the cells in the body.

Researchers at UCD - in collaboration with colleagues at University of Sheffield, Queen Mary University of London and Genentech - looked at a type of immune cell, called a macrophage, that has a role in the inflammation stage, but also in the growth and healing phase. These cells are like conductors of an orchestra: they tell the other immune cells when to fight infection but also when to turn off “fight” mode and to turn on “healing” mode. Therefore, when they stop working properly, the whole immune system can go out of tune.

This happens in many auto-immune diseases, including rheumatoid arthritis. The research team previously found a difference in the DNA of people living with rheumatoid arthritis compared to those without it. They showed that people with this difference made less of a protein then called C5orf30 in their macrophages (those conductors of the immune system). As a result of this research, the protein was given the official name MACIR (MACrophage Immunometabolism Regulator).

Dr Kevin Sheridan, Dr David OConnell, Prof Gerry Wilson and Dr Emma Dorris marking the naming of the MACIR gene. Absent is Prof Denis Shields.

What does C5orf30 do?

They were very interested in this odd little protein, as it is found in all animals with a backbone (vertebrates) and has not changed very much throughout evolution, yet nobody knows what it does. In science, to figure out what a protein does we use powerful computers to basically ask the very simple questions: Does it look like a duck, act like a duck, or quack like a duck? If the answer is yes, you test the hypothesis that it is a duck. MACIR neither looks nor quacks like any protein (or duck) known.  So to figure out what it does the researchers asked, how does it act?

Working with our colleagues in Queen Mary, University of London, they looked at the MACIR in the most severely affected joints of people newly diagnosed with rheumatoid arthritis. They found that when these people had more inflammation, they had less MACIR. This led them to test what MACIR does in the laboratory. Immune cells are found in the blood. From blood samples, they separated out the macrophage cells and used an experimental method to stop MACIR from being made. This showed that indeed, when the MACIR protein is reduced, the macrophages went very out of tune. They were no longer able to properly switch from “fight” mode to “healing” mode.

Next, to see what MACIR protein did in response to tissue damage, they used a zebrafish model. You may be surprised to find that this very little fish has an immune system similar to humans. The researchers used experimental techniques to make its macrophage glow red. At its larval stage, this fish is also see-through, so they could see where its glowing red macrophages go in the fish. In response to an injury to its tail, far more macrophages rush to the injury site when the MACIR protein is turned down. Again, this is showing that less MACIR make the macrophages more in the mood to “fight”.

This study is important because a new protein involved in conducting the immune response has been found. By figuring out how this interesting little protein works, not only were they finally able to give C5orf30 the name MACIR but the researchers were able to better understand the fine-tuning of the immune system and how to bring it back into harmony when it gets out of tune.

Will this lead to a new drug for rheumatoid arthritis and other autoimmune diseases?

It is far too early to tell yet but the prospects are certainly exciting. Researchers are currently investigating what happens when MACIR is increased; does it make cells less likely always to want to “fight” when they should not and encourage them to “heal”? How is this best done? Can it be controlled?

These are the questions that have to be answered in order to know if MACIR can be used directly in new therapies to improve the treatment of rheumatoid arthritis and other inflammatory diseases.

Funders: HRB, Arthritis Ireland and Irish Research Council

Related academic journal articles 

• Dorris, ER et al (2019). The Autoimmune Susceptibility Gene C5orf30 Regulates Macrophage-Mediated Resolution of Inflammation. The Journal of Immunology, 18 January 2019

• Muthana, M et al (2015). C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis. PNAS, 15 September 2015, 112 (37), pp.11618-11623