Systemic lupus erythematosus (lupus) is a multi-organ autoimmune disease with 5-10% mortality in 10 years. Both skin and kidney (lupus nephritis, LN) are severely affected and sensitivity to ultraviolet (UV) sunlight rays affecting ~ 80% of patients can lead to LN flares. The cellular and molecular mechanisms linking skin inflammation caused by UV light and kidney injury are unknown. The overall objectives in this proposal are to: (i) demonstrate mechanisms by which neutrophils migrating from UV-exposed skin damage glomerular and tubular cells to trigger LN flares, (ii) elucidate the role of a novel CD177high neutrophil population in kidney injury, and (ii) define the role of UV-induced type I interferon (IFN-I) response on neutrophil interactions with and damage of kidney structural cells, on a single-cell basis. The central hypothesis is that neutrophils recruited to the kidney following skin UV exposure mediate acute podocyte and distal tubular loss and injury, and lead to chronic mesangial fibrosis potentiated by type I interferon. The rationale for this project stems from the gap in the knowledge of how neutrophils mediate kidney injury in lupus. The central hypothesis will be tested by pursuing two specific aims: 1) Define the mechanisms of neutrophil-mediated lupus nephritis flares caused by skin exposure to UV light and 2) Define the role of UV-induced IFN-I on neutrophil interactions with and damage of kidney structural cells. In Aim 1, single cell RNA sequencing (scRNAseq)of renal structural cells, multiplexed immunofluorescence staining of the kidney tissue, and kidney proteomics, will be applied to define how neutrophils (e.g., CD177hi) injure renal endothelium and epithelium in an autoantibody-mediated and a photosensitive model of LN. In Aim 2, scRNAseq of kidney structural cells and neutrophils, in the absence of global or neutrophil-specific IFN-I signaling, will define IFN-I driven genes and pathways, as well as neutrophil-kidney cells ligand-receptor interactions, involved in UV-triggered kidney injury in LN models. The research proposed in this application is innovative because it will identify molecular and cellular targets that link local skin and distal renal injury. The proposed research is significant because it is expected to provide a strong scientific rationale to target specific pathways of neutrophil-mediated inflammatory mechanisms and downstream structural cell injury for therapeutic purposes in LN flares.