Nardilysin: classical functions and new horizons in autoimmunity

Autoimmune diseases affect 5-10% of the global population, with a prevalence of 13% in women and 7% in men. Despite advances in immunology, the molecular basis of immune dysregulation remains limited. Nardilysin (NRD convertase, NRDc), a zinc-dependent metalloendopeptidase, has been identified as an enzyme involved in this dysregulation. Recent studies have identified NRDc dysregulation as a shared feature across type 1 diabetes (T1D), rheumatoid Arthritis (RA), and vitiligo, though the specific mechanism implicated differs by the disease involved. Reported roles for NRDc include modulating the release of the immune checkpoint protein VTCN1 (B7-H4), modulation of pro-inflammatory cytokines, and activation of ADAM17-mediated release of TNF-α and its receptors. While NRDc is recognized for its role in immune signaling, gene transcription, cell differentiation, proliferation, homeostasis, thermogenesis, and metabolism, a unified framework connecting NRDc's multifaceted enzymatic activity to autoimmunity is currently lacking. We review current literature to construct such a framework, positioning it as hypothesis-generating by outlining specific, testable predictions to guide future investigation. Based on the literature, we propose that NRDc functions as a crucial molecular indicator and a therapeutic interface, rather than just a bystander enzyme.