A major research collaboration, led by the MRC Centre for Medical Mycology at the University of Exeter, has focused on how immune cells sense their environment. This triggers finely tuned responses to protect against disease and infection, and to reduce inflammation that damages cells. The new research, published in the world-renowned journal Nature and funded by the Medical Research Council and Wellcome, looked at the behaviour of a receptor known as MICL and its role in both preventing inflammation and protecting against infection. In practice, the scientists found that MICL is a receptor that causes severe inflammatory diseases when its function is impaired. This opens the door to the development of new therapies that target MICL, which could reduce the severity of certain inflammatory diseases and protect against infection.
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 cell’s activation. This is an important function, as overactivation of immune cells can lead to cell damage and the development of autoimmune diseases if left unchecked. The team went on to demonstrate the essential role that MICL plays in regulating inflammation in arthritis and some other autoimmune diseases. The new research, conducted in mice and verified in patients, focused on the function of MICL in the most abundant white blood cells called neutrophils. As a result of an autoimmune disease or infection, neutrophils can undergo NETosis, a form of programmed cell death that is critical for controlling infection but is highly inflammatory.
The team found that MICL can sense it, and its inhibitory activity prevents other neutrophils from dying in this way. MICL directly recognizes DNA in extracellular traps (NETs); this interaction is critical for regulating neutrophil activation. Loss or inhibition of MICL function leads to uncontrolled NET formation through the ROS-PAD4 pathway and the development of an auto-inflammatory feedback loop. Cell death from NETosis has been linked to inflammatory diseases such as lupus, psoriasis, and rheumatoid arthritis. These inflammatory diseases lead to the production of antibodies that bind to MICL, preventing its inhibitory function and causing more severe disease. In contrast, the study showed that increasing NETosis by blocking MICL function can protect against infections, such as those caused by fungi. In mice with arthritis, the team showed that genetic loss of MICL led to more severe disease due to excessive formation NETs.
More severe disease also occurred in normal mice when MICL-targeted antibodies were applied. Indeed, more severe disease was also observed in human arthritis patients who possessed MICL-targeted antibodies. Thus, NET recognition by MICL represents a key autoregulatory pathway that controls neutrophil activity and NET formation. MICL belongs to the C-type lectins (it is also called CLEC12A). Neutrophils express innate immune receptors belonging to the C-type lectins, such as CLEC2, Mcl (CLEC4D), Mincle (CLEC4E), MDL-1 (CLEC5A) and Dectin-1 (CLEC7A). Dectin-1 appears to act as the major receptor for fungal β-glucans; Mincle is a multifunctional receptor that recognizes Malassezia fungi and mycobacterial structures while MDL-1 is probably involved in viral recognition. There is not much information about these receptors, although it could be hypothesized that they represent the bridge between external pathogens and the onset of autoimmunity.
MICL has already been shown to participate in the inflammation that characterizes rheumatoid arthritis, where it also acts as an autoantigen. Antibody blockade of MICL delays the onset of EAE (the laboratory form of multiple sclerosis) and attenuates the severity of the disease by compromising the infiltration of myeloid cells into the central nervous system and restoring positive immunity. More recently, its presence seems necessary because malaria plasmodium can infiltrate the nervous system to cause the “cerebral” form of the disease. This opens a window to the treatment of this dangerous infectious disease that is still widespread throughout Africa and Asia. Finally, there are recent data indicating that the cellular presence of MICL can act as a prognostic marker for acute myeloid leukemia (AML), whose bone marrow precursors are precisely those that will give rise to neutrophil granulocytes.
Low MICL expression on leukemic blasts appears to be independently associated with a lower probability of achieving complete remission after 1 cycle of induction chemotherapy, a shorter event-free survival, as well as overall survival, indicating potential prognostic properties of the expression of this receptor itself. The lack of its expression on normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, could result in lower toxicity with regard to cytopenias, making MICL an attractive target for innovative immunotherapies alongside classical ones such as CAR-T.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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