Identifying Myeloid‐Derived Suppressor Cells and Lipocalin‐2 as Therapeutic Targets for Intervertebral Disc Degeneration

Abstract Inflammation is a hallmark of intervertebral disc degeneration (IVDD) characterized by immune cell infiltration and cytokine secretion. Stage‐specific transcriptomic analyses of IVDD via single‐cell RNA sequencing (scRNA‐seq) have primarily focused on nucleus pulposus cell phenotypes but not immune subpopulations. In other disease contexts, integrating genome‐wide association studies (GWAS) with scRNA‐seq data has provided insights on pathomechanisms in relation to specific cellular subpopulations via single‐cell disease relevance scores (scDRS). However, such an approach remains to be applied to IVDD. Here, the stage‐ specific analysis of IVDD in relation to Pfirrmann grading revealed a key transition in immune cells from a preponderance of LCN2 high myeloid‐derived suppressor cells (MDSCs) during early degeneration to a surge of proinflammatory IL1B+ macrophages in advanced IVDD. scDRS implicated IL1B+ M1‐like macrophages as a GWAS risk‐enriched subpopulation associated with disease, while functional validation indicated an immunomodulatory effect of LCN2 high MDSCs via ANXA1‐mediated inflammation suppression. Accordingly, LCN2 knockout mice exhibit accelerated IVDD, whereas recombinant LCN2 promoted macrophage polarization in vitro to the reparative phenotype by enhancing ANXA1 / Arginase‐1 expression and countering LPS/IFN‐γ‐induced pro‐inflammatory phenotype. This work identifies LCN2 high MDSCs as an immunoprotective subpopulation in early IVDD and highlights a potential role of LCN2 as a novel therapeutic agent.