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

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 LCN2high 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 LCN2high 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 LCN2high MDSCs as an immunoprotective subpopulation in early IVDD and highlights a potential role of LCN2 as a novel therapeutic agent.