Assistant Professor Geisel Sch. of Med. at Dartmouth, United States
Introduction/Rationale: 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.
