UVB Irradiation Empowered Neturophils With Transmigratory and Proinflammatory Abilitites to Mediate Acute Lupus Flares With Skin and Kidney Inflammation

Document Type

Conference Proceeding

Publication Date

8-2024

Publication Title

Journal of Investigative Dermatology

Abstract

Ultraviolet B (UVB) triggers acute lupus flares, but the underlying mechanisms are not well understood. We have reported that UVB exposure induces skin inflammation with neutrophil infiltration and neutrophil extracellular trap (NET) formation in wildtype mice. Here, we found that UVB exposure induced acute lupus flares with both skin and kidney inflammation and proteinuria in asymptomatic young female lupus-prone mice. To understand this, we analyzed infiltrated neutrophils and NETs in the skin and kidneys of UVB-irradiated MRL/lpr mice, as well as UVB-irradiated neutrophils in vitro. We found increased skin thickness, immune cell infiltration, neutrophil NETosis, and deposition of NET-associated IFNα, IFNγ, IL-17A, or C3 both in the skin and kidneys. Infiltrated cells in skin positively correlated with proteinuria (r=0.57, p<0.05), indicating a link between skin infiltrates and kidney injury. Neutrophils exposed to UVB or platelet-activating factor in vitro upregulated cytokines and C3, partially co-expressing CXCR4 and CX3CR1, chemokine receptors that could mediate neutrophil transmigration from skin to kidneys. In our preliminary study, application of the CXCR4 inhibitor IT1t significantly attenuated neutrophil infiltration and accumulation of NETs and NET-associated cytokines/C3, including IFNα (3.2% vs 0.43% area in UVB vs IT1t+UVB mice, P<0.01) in kidneys and decreased proteinuria in UVB-irradiated MRL/lpr mice. By directly targeting NETosis through a novel nuclear envelop regulation strategy, we found that controlling NETosis attenuated deposition of NET-associated cytokines and C3 in the skin and kidneys of UVB-irradiated MRL/lpr-lmnb1Tg mice with nuclear lamin B overexpression. NET-associated IFNα (r=0.49, p<0.01) or C3 (r=0.38, p<0.05) in kidneys correlated with proteinuria. Thus, UVB irradiation led to neutrophil infiltration, transmigration, and NETosis, mediating skin and kidney inflammation in acute lupus flares.

Volume

144

Issue

8 Suppl

First Page

S172

Comments

Society for Investigative Dermatology Annual Meeting, May 15-18, 2024, Dallas, TX

DOI

10.1016/j.jid.2024.06.1157

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