Background/Purpose: Sensitivity to ultraviolet B (UVB) light affects ~70% of SLE patients and exacerbates both skin disease and systemic flares, including lupus nephritis (LN). Our findings that neutrophils are the dominant infiltrating immune cell in the skin after exposure to UVB light together with the recent discovery that neutrophil gene signature is the strongest predictor of active SLE disease prompted the hypothesis that neutrophils are the pathogenic link between UVB light-induced inflammation in the skin and kidney injury in SLE.

Methods: Mice (C57BL/6J, 3-4mo) were exposed to a single dose of UVB light (500mJ/cm2, 280-320 nm). Skin infiltrating neutrophils in photoactivatable mice (UBC-PA-GFP) were photoconverted with violet light (~415nm) 1 day after UVB light exposure. Individual mice were euthanized on 1, 2, or 6 days after UVB and perfused with saline; non-irradiated mice were used as controls. Immune cells isolated from the skin, bone marrow (BM), blood, lung, and kidney were profiled by flow cytometry. Gene expression was evaluated by QPCR, plasma protein concentration by Legendplex Inflammatory Panel, and proteinuria by Bradford assay.

Results: Acute exposure to UVB light caused a 10-fold increase in neutrophil numbers in the skin, associated with their precipitous egress from the BM and a 5-fold increase in circulating neutrophils. Unexpectedly, UVB light injury in the skin caused neutrophil migration to peripheral organs, including the lung and kidney, with up to 10-fold increase in neutrophil numbers in the kidney. Extensive gene profiling of the skin tissue revealed a broad local cutaneous inflammatory response to UVB light injury, while proteomic analysis of plasma samples identified IL17A as the dominant inflammatory mediator found in circulation 6-24hr after skin exposure to UVB light.

Relevant to SLE pathogenesis, neutrophil infiltration into the kidney was accompanied by endothelial activation and inflammation: increased expression of adhesion molecules VCAM-1 and E-Selectin, as well as inflammatory proteins IL1β, s100A8/9, and s100A6. Moreover, we detected increased early (day 1-2) expression in Ngal and Kim1, markers of kidney injury in LN, as well as elevated urine protein levels, findings indicating that skin exposure to UVB light triggers transient kidney damage. Neutrophils in distal sites late (day 6) after UVB light injury demonstrated two phenotypes: aged CXCR4^hi and reverse migrating ICAM1^hiCXCR1^lo. In the kidney, presence of CXCR4^hi neutrophil population followed expression of CXCR4 ligand, CXCL12, another marker of kidney injury. In the photoactivatable mouse model, photoconverted GFP+ skin infiltrating neutrophils were detected in the kidneys of mice one day after UVB light exposure.

Conclusion: Our findings provide several novel insights into the neutrophil response to UVB light: i) localized skin injury triggers systemic neutrophil migration, accompanied by inflammatory response and transient kidney injury and ii) presence of CXCR4^hi and ICAM1^hiCXCR1^lo neutrophil populations in peripheral organs suggests that a subset of activated skin-infiltrating neutrophils has migrated to distal organs via reverse transmigration.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/uv-light-stimulates-a-systemic-neutrophil-response-associated-with-transient-kidney-injury/