Since the discovery of IDO2 in 2007, there has been ongoing effort to understand whether this new KP enzyme functions similarly to its closely related family member, IDO1, or if there is an evolutionary or physiological need for a second IDO enzyme with distinct roles. To date, IDO2 has been implicated in immune regulation, particularly in cancer and autoimmune diseases. Despite nearly two decades of research on IDO2, much remains to be learned about its contribution to human diseases. This month, we highlight IDO2’s role in autoimmune diseases.
Building on previous work, Dr. Mandik-Nayak’s team identified novel non-enzymatic functions of IDO2 in mediating autoimmune diseases through interactions with several binding proteins specific to IDO2 but not IDO1. In this featured study, Peng W. et al. demonstrated that one of these binding proteins, Runx1, interacts with IDO2 to drive autoimmune arthritis in a preclinical model.
In brief, using a combination of transgenic and knockout (KO) mouse models, the study showed that:
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- IDO2 binds to Runx1 in the cytoplasm and prevents its translocation to the nucleus in B cells (a key immune cell expressing IDO2).
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- Runx1 needs to be present in the nucleus of B cells to inhibit autoreactive B cell processes.
In other words, strategies that inhibit IDO2 from binding to Runx1 or promote Runx1’s translocation into the nucleus of B cells could suppress autoantibody production and alleviate arthritis. Collectively, these findings provide new perspectives on the role of IDO2 in the immunobiology of autoantibodies and autoimmune diseases. Far from being a mere subsidiary, IDO2 likely complements IDO1 in immune regulation, potentially reflecting an evolutionary advantage. Exploring the therapeutic potential of IDO2 inhibition in autoimmune diseases in a clinical setting will be an exciting next step!