Neutrophil—endothelial crosstalk after skin UV exposure orchestrates renal repair in health but drives profibrotic remodeling in lupus 2258618

Abstract Introduction Neutrophils can remigrate from UV-exposed skin to the kidney, but how they instruct renal structural cells is unclear. We tested whether tissue context, healthy vs lupus-like, programs neutrophil—endothelial interactions and phenotypes that tip the skin—kidney axis toward repair or inflammation. Methods Female B6 mice received one UVB dose (500 mJ/cm²). Kidneys and enriched neutrophils underwent 10x scRNA-seq at baseline and day 2. Renal neutrophils in B6 and MRL-lpr mice were profiled by flow cytometry; neutrophils were depleted with anti-Ly6G. Human studies used Visium on LN biopsies and DNA-methylation of urine cells. Results In B6 mice, UV expanded a glomerular endothelial cluster which upregulated angiogenesis/vascular-development transcriptional programs. UV-recruited neutrophils upregulated pro-angiogenic programs and neutrophil depletion blunted renal angiogenic and wound-healing signatures. Ligand—receptor analysis identified Cd177—Pecam1 as a key neutrophil—endothelial interaction. In lupus-like kidneys, UV induced TGFβ/Wnt pathways, which were suppressed with neutrophil depletion. Flow cytometry showed expansion of SiglecF+ neutrophils and loss of inhibitory receptor CD371 (Clec12a) in lupus conditions. Conversely, B6 renal neutrophils upregulated CXCR4 and CD371, consistent with a regulatory/repair phenotype. In lupus nephritis (LN) biopsies, active skin disease was associated with increased renal neutrophil signatures and increased angiogenesis and fibrosis pathway scores in neutrophil-rich regions. Moreover, urinaryl neutrophils were higher in lupus patients with active skin disease. Conclusion Acute UV mobilizes neutrophils that engage renal endothelium, eliciting pro-angiogenic remodeling in health. In lupus-like kidneys, this crosstalk is reprogrammed toward profibrotic/inflammatory signaling. These findings define a UV-driven skin-kidney axis and identify neutrophil checkpoints and endothelial contacts which may be implicated in renal injury in lupus. Funding Source CDMRP Lupus Research Program, NIGMS P20GM130454 Topic Categories Immune Mechanisms of Human Disease (HUM)