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The discovery of new regulator-affecting immune cells could lead to novel treatments to reduce inflammation in diseases, including arthritis and severe COVID-19.

The new research, carried out by a large collaboration including researchers at the University of Glasgow, focused on how immune cells sense their environment –activity that triggers responses which are finely balanced, to protect against disease and infection, and to reduce cell-damaging inflammation.

The study, which was led by the University of Exeter’s MRC Centre for Medical Mycology and published in Nature, looked at the behaviour of a receptor known as MICL and its role in both preventing inflammation and protecting against infection. The research team found that the healthy functioning of MICL was key to preventing against inflammatory diseases such as arthritis.

While most receptors in the immune system sense their environment and send signals to cells, telling them to activate in response to changes such as infection or tissue damage, the team’s work revealed that MICL does the opposite, inhibiting the activation of the cell. This is an important function, as over-activation of cells can lead to cell damage and the development of auto-immune diseases if left unchecked. The team went on to demonstrate the essential role that MICL plays in regulating inflammation in severe COVID 19, as well as arthritis and some other autoimmune diseases.

The new research, conducted in mice and verified in patients, focused on the function of MICL present on the most abundant form of immune cell called a neutrophil. As a result of autoimmune disease or infection, neutrophils can undergo NETosis, a form of programmed cell death which is key for controlling infections but is very inflammatory. The team has found that MICL is able to detect this, and its inhibitory activity prevents more neutrophils from dying in this way.

In mice with arthritis, the group showed that genetic loss of MICL led to more severe disease due to the excessive formation of NETs. More severe disease also occurred in normal mice when antibodies targeting MICL were applied. Indeed, more severe disease was also seen in human arthritis patients who possessed antibodies targeting MICL, and the researchers could directly show that these patient antibodies drove exacerbated inflammatory response, using cell samples in labs.

NETosis cell death has been linked to several inflammatory diseases in humans, including Lupus, Rhematoid arthritis and severe COVID. These inflammatory diseases lead to the production of antibodies that bind to MICL, preventing its inhibitory function and resulting in more severe disease. Conversely, the study showed that increasing NETosis by blocking MICL function can protect against infection, such as those caused by fungi.

Lead author Mariano Malamud, from the University of Exeter, said: “We’ve discovered that MICL is a key receptor that causes severe inflammatory disease when its functions are altered. This opens the door to the development of new therapies that target MICL, which could reduce the severity of inflammatory diseases and protect against infection.”

Professor Iain McInnes, co-author of the study and Head of the College of Medical, Veterinary & Life Sciences at the University of Glasgow, said: “This study provides a vital new clue that can guide us in our search for the pathways that lead to the development of rheumatoid arthritis and other immune diseases. The paper suggests that loss of immune balance through the behaviour of the MICL receptor could be one of the immune pathways that collectively lead to the development of rheumatoid arthritis in some individuals.

“The study makes use of the Scottish Early Rheumatoid Arthritis Cohort which is a Scotland wide effort on the part of NHS and academic consultants and most importantly our patients, to gather information and samples from people in the early years after they developed rheumatoid arthritis and thereby allow us to better understand the disease. Further studies are now necessary to understand how best we can capitalise on this to improve treatments in future.”

Senior author Professor Gordon Brown, from the University of Exeter, said: “We’ve been working on how immune cells sense their environment for over 20 years, and this breakthrough is really exciting, revealing how the inhibition of inflammatory processes is finely balanced between controlling infection and the development of autoimmune disease”

The paper, “Recognition and control of Neutrophil Extracellular Trap formation by MICL’, is published in Nature. The study is funded by and funded by the Medical Research Council and Wellcome.

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Enquiries: ali.howard@glasgow.ac.uk or elizabeth.mcmeekin@glasgow.ac.uk

First published: 14 August 2024