Background/Purpose: The majority of SLE patients are sensitive to ultraviolet light (UV), which can lead to local and systemic inflammation, including lupus nephritis (LN) flares. While we previously showed that neutrophils remigrate from UV-exposed skin to the kidney, how these neutrophils impact renal structural cells remains unclear. We hypothesize that neutrophils play a reparative role in healthy kidneys but exert pro-inflammatory effects in lupus-like kidneys.

Methods: ScRNA-seq was performed by 10X Genomics on saline-perfused, digested kidneys and enriched neutrophils from 3-month-old female B6 mice before and 2 days after a single UVB exposure (500 mJ/cm²). Clustering (Seurat), pathway analysis (clusterProfiler), and ligand-receptor analysis (CellChat) were used. Neutrophils were profiled by flow cytometry 6 days post-UVB in 3-month-old female B6 and MRL-lpr mice. Spatial transcriptomics (Visium) was performed on class III/IV LN kidneys, and urinary immune cells were quantified by DNA methylation deconvolution.

Results: Acute skin exposure to UV in B6 mice resulted in the expansion of renal glomerular endothelial cells, confirmed by increased CD31 staining. Of the most highly upregulated pathways in the expanded glomerular endothelial cluster were regulation of angiogenesis and vascular development, which were validated by increased angiogenesis transcriptional scores and expression of Angpt2, Angptl1, and Angptl4. Ligand-receptor analysis of the structural cells and enriched neutrophils showed significant increase in neutrophil-endothelial interactions (Cd177-Pecam-1). Neutrophil scRNAseq and flow cytometry at D2 showed UV skin exposure recruits CD177hi neutrophils that infiltrate the kidney. On day 6 post-UV, neutrophils in B6 kidneys had increased surface expression of CXCR4 and the inhibitory receptor CD371 (Clec12a). In contrast, CD371 levels were significantly decreased on the kidney infiltrating neutrophils of MRL-lpr mice after UV and no change in CXCR4 was seen. Spatial transcriptomics analysis of LN patient kidney biopsies revealed increased intra-glomerular neutrophil signature in patients with active skin disease and increased angiogenesis pathway score. In support of neutrophil-mediated skin-kidney crosstalk in SLE, intrarenal neutrophil levels were higher in lupus nephritis (LN) patients with active skin disease at the time of kidney biopsy than in LN patients without cutaneous involvement. In a subset of SLE patients without clinical signs of LN, high urinary neutrophils were associated with active skin disease, suggesting distal inflammation in the skin could contribute to subclinical renal processes in SLE.

Conclusion: Our findings reveal that UV exposure triggers glomerular endothelial expansion and pro-angiogenic signaling in the kidney, accompanied by increased recruitment of CD177⁺ neutrophils. The regulatory phenotype of renal neutrophils post-UV in health kidneys is lost in lupus-like kidneys. Spatial and urinary profiling in LN and SLE patients supports a model of neutrophil-mediated skin-to-kidney crosstalk, implicating cutaneous flares in both clinical and subclinical renal involvement.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/from-skin-to-kidney-neutrophil-mediated-crosstalk-links-cutaneous-injury-to-renal-inflammation-and-vascular-remodeling-in-lupus/