Inhibiting NETosis Through Nuclear Envelope Regulation Decreased UVB-Induced Inflammation in the Skin and Distant Kidneys in Lupus-Prone Mice

Document Type

Conference Proceeding

Publication Date

8-2026

Publication Title

Journal of Investigative Dermatology

Abstract

Ultraviolet B (UVB) overexposure triggers lupus flares, provoking skin and systemic inflammation in organs such as the kidneys. Building on our finding that UVB induces neutrophil infiltration and NETosis in the inflamed skin of wild-type mice, we investigated whether NETosis is involved in UVB-induced skin and systemic inflammation. 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. UVB irradiation in lupus-prone mice induced skin and renal inflammation with proteinuria, characterized by neutrophil infiltration, NETosis, and elevated levels of pro-inflammatory cytokines and complement C3. Infiltrating neutrophils in the skin positively correlated with proteinuria (r=0.83, p< 0.01), suggesting that skin neutrophil infiltration contributes to kidney injury. Genetic deletion of PKCα—a regulator of the nuclear envelope—inhibited NETosis and significantly ameliorated skin and kidney inflammation and proteinuria by reducing NET-associated cytokines and C3. Mechanistically, UVB irradiation increased proinflammatory cytokines and the transmigration receptor CXCR4, a potential pathway for skin-kidney communication, in isolated neutrophils in vitro and in lupus-prone mice in vivo. Using photoconversion tracking in kikGR;CXCR4+/- mice, we demonstrated that CXCR4 deficiency reduced neutrophil transmigration from the skin to the kidneys and decreased proteinuria. Furthermore, pharmacological inhibition of CXCR4 with IT1t attenuated acute kidney inflammation and reduced the renal accumulation of neutrophils, NETs, C3, and IFNα (3.2% vs. 0.43% area in UVB vs. IT1t+UVB mice, P< 0.05). Therefore, this study reveals that neutrophil transmigration and NETosis drive UVB-triggered skin and kidney inflammation, highlighting them as potential therapeutic targets. Remarkably, nuclear envelope regulation represents a promising strategy for controlling NETosis in lupus.

Volume

146

Issue

8 Suppl

First Page

S121

Comments

Society for Investigative Dermatology (SID) Annual Meeting, May 13-16, 2026, Chicago, IL

Last Page

S121

DOI

10.1016/j.jid.2026.06.729

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