The identification of a novel regulator that influences immune cells might pave the way for innovative treatments aimed at alleviating inflammation in conditions like arthritis and severe COVID-19.
A significant research partnership, spearheaded by the MRC Centre for Medical Mycology at the University of Exeter, has explored how immune cells perceive their surroundings. These responses are delicately balanced, essential for combating diseases and infections while minimizing harmful inflammation.
The recent study, featured in Nature and supported by the Medical Research Council and Wellcome, examined the behavior of a receptor named MICL, and its function in both curbing inflammation and safeguarding against infections.
Dr. Mariano Malamud, the lead author from the University of Exeter, stated: “We’ve found that MICL is an important receptor that triggers serious inflammatory conditions when its function is disrupted. This discovery paves the way for new treatments that focus on MICL, potentially lessening the intensity of inflammatory illnesses and providing protection against infections.”
Typically, receptors in the immune system detect environmental changes and signal cells to activate in response to things like infections or tissue damage. However, the team found that MICL performs the opposite role by inhibiting cell activation. This function is crucial because excessive cell activation can cause damage and lead to autoimmune diseases if not properly regulated. The researchers demonstrated MICL’s vital role in managing inflammation in severe COVID-19, arthritis, and certain other autoimmune disorders.
This study, conducted on mice and confirmed in human patients, examined the function of MICL situated on neutrophils, the most prevalent type of immune cell. In cases of autoimmune diseases or infections, neutrophils can undergo NETosis, a programmed cell death that is essential for fighting infections but also induces significant inflammation. The study found that MICL can sense this process, and its inhibitory effects prevent additional neutrophils from dying in this manner.
NETosis has been associated with various inflammatory diseases in humans, including lupus, rheumatoid arthritis, and severe COVID-19. These conditions trigger the production of antibodies that bind to MICL, obstructing its inhibitory role and leading to more severe health issues. In contrast, the study revealed that enhancing NETosis through MICL blockage could offer protection against infections like those caused by fungi.
In mouse models of arthritis, the research team demonstrated that the absence of MICL resulted in more severe disease due to excessive NET formation. Similar worsening of the disease was observed in normal mice treated with antibodies targeting MICL. Furthermore, more severe conditions were observed in arthritis patients with antibodies against MICL, and researchers were able to show that these antibodies directly contributed to heightened inflammatory responses in lab cell samples.
Professor Gordon Brown, the senior author from the University of Exeter, commented: “For over two decades, we have been investigating how immune cells perceive their environment, and this discovery is incredibly exciting. It highlights how the inhibition of inflammatory processes must be meticulously balanced to manage infections and prevent the onset of autoimmune diseases.”
The study is titled “Recognition and control of Neutrophil Extracellular Trap formation by MICL” and is published in Nature.
