Kidney-infiltrating proteinase 3-positive granulocytes are abundant in lupus nephritis.

Abstract

Active proliferative lupus nephritis (LN) is associated with elevated urinary neutrophil granule proteins such as proteinase 3 (PR3), implicating active cellular degranulation in LN. Yet, mature neutrophils are rarely observed in LN biopsies, raising the possibility of an unrecognized cellular source. We aimed to identify and characterize PR3-expressing myeloid cells in LN kidneys using a spatially resolved multi-omics approach. Serial immunohistochemistry (10-plex) and spatial transcriptomics were employed to assess the distribution of PR3+ cells across renal tissue and characterize their cellular phenotype. PR3+ cells were abundant in LN kidney biopsies, but with marked inter-patient heterogeneity. These cells were predominantly localized to the tubulointerstitium and showed similar distribution in both proliferative and membranous LN. In contrast, intraglomerular PR3+ cells were enriched in proliferative LN and correlated with the NIH Activity Index. Phenotype analysis identified four subsets of PR3+ cells, consistent with a monocyte/neutrophil lineage. Most PR3+ cells lacked multilobate nuclei, distinguishing them from mature neutrophils, suggesting that these cells may be overlooked by conventional light microscopy. PR3+ myeloid cells are a prominent and heterogeneous population in lupus nephritis. While intraglomerular PR3+ cells were specific to proliferative LN and correlated with histologic activity, the widespread presence of PR3+ cells in the tubulointerstitium suggests broader involvement in renal inflammation than previously recognized. These findings reveal a potentially overlooked immune cell population that may contribute to renal injury in LN.