Session Type: Abstract Session
Session Time: 10:00AM-10:50AM
Background/Purpose: Sensitivity to ultraviolet (UV) light affects up to 80% of SLE patients and can exacerbate systemic disease flares, including lupus nephritis (LN). Our findings that neutrophils are the dominant skin infiltrating immune cell after exposure to UV light together with the recent discovery that neutrophil gene signature is the strongest predictor of active SLE prompted the hypothesis that neutrophils are a key pathogenic link between UV-induced inflammation in the skin and kidney injury in SLE.
Methods: Mice (C57BL/6J, 3-4mo) were exposed to one dose of UVB (500mJ/cm2). Individual mice were euthanized on 1, 2, or 6 days after UV and perfused with saline; non-irradiated matched mice were used as controls. Immune cells from the skin, bone marrow, blood, lung, and kidney were profiled by flow cytometry (FC). Gene expression was evaluated by QPCR, plasma protein concentration by Legendplex Inflammatory Panel, and proteinuria by Bradford assay. Immunofluorescence staining of fixed kidney tissue was performed. Photoactivatable (UBC-PA-GFP) mice were used to photoconvert skin infiltrating neutrophils to GFP+ cells and track them systemically by FC.
Results: Following acute skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, where we observed a 10-fold increase in neutrophil numbers, mainly localized to the tubulointerstitium. Neutralization of IL-17A, which increased 10-100-fold in circulation after exposure to UV light (6-24 hr), inhibited neutrophil migration to the kidney. Relevant to SLE pathogenesis, neutrophil infiltration into the kidney was accompanied by renal inflammatory and injury processes: increased expression of adhesion molecules VCAM-1 and E-Selectin, inflammatory proteins IL1β, s100A8/9, and s100A6, tubular injury markers Ngal and Kim1, as well as elevated urine protein levels. Kidney infiltrating neutrophils produced reactive oxygen species (ROS) and inhibition of neutrophil mobilization by G-CSF neutralization resulted in significant reductions in the expression of adhesion molecules, inflammatory cytokines, and kidney injury markers. Using a mouse model with photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin, expressing the pro-inflammatory phenotypes of aged (CXCR4hi) or reverse-transmigrating (ICAM1hiCXCR1lo) cells. We identified elevated levels of CXCR4hi and ICAM1hiCXCR1lo neutrophils in SLE patients particularly within the low-density granulocytes (LDG).
Conclusion: Our study provides several novel findings that could help explain how exposure to sunlight impacts the kidney: i) skin exposure to UV light triggers IL17-A-dependent neutrophil migration to the kidney, accompanied by renal inflammatory and injury responses, ii) neutrophils are directly implicated in subclinical kidney injury as neutralization of G-CSF abrogated renal inflammation and injury, iii) a subset of activated neutrophils has migrated to the kidney via reverse transmigration and is found in SLE patients, suggesting a pathogenic role for these neutrophil populations in lupus.
To cite this abstract in AMA style:Skopelja-Gardner S, Tai J, Sun X, Tanaka L, Kuchenbecker J, Mustelin T, Elkon K. Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UV Light [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/neutrophils-mediate-kidney-inflammation-following-acute-skin-exposure-to-uv-light/. Accessed February 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophils-mediate-kidney-inflammation-following-acute-skin-exposure-to-uv-light/