Resident immune cell neighborhoods associate with protein kinase pRIPK3 and fatty acid ligase FACL4 expression during cell injury in ANCA associated vasculitis and lupus nephritis.

Abstract

Tubulointerstitial injury is a key determinant of kidney prognosis and progression to chronic kidney disease in both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lupus nephritis (LN). Identification of immune cell-induced injury of cells outside the glomerulus in vasculitic kidney diseases may inform potential targets for therapeutic interventions. To identify these cells, kidney biopsy samples from 15 patients (5 AAV, 5 class III and IV LN, 5 reference) were analyzed at single cell resolution using Imaging Mass Cytometry. Unbiased clustering of all 106,455 cells identified the expected resident tubule, endothelial, vascular and stromal cells, along with a marked increase in interstitial immune cells. Quantification of cell marker expression in resident cell clusters revealed downregulation of cell differentiation markers and upregulation of phosphorylated protein kinase RIPK3 and fatty acid ligase FACL4 in multiple tubule segments and endothelial cells in both AAV and LN compared to reference samples (non-tumor regions of nephrectomy samples). Spatially, these injury markers were increased in resident cells that were immediately adjacent to immune cells and in particular T cells. Our hypothesis-generating study shows that distinct immune cells are spatially associated with specific cell injury responses in the tubulointerstitium and identify pRIPK3 and FACL4 expression as potential integral components of that injury and cell death response.