Neutrophil extracellular traps drive acute lupus flares with skin and kidney inflammation triggered by ultraviolet irradiation

Sunlight overexposure triggers acute lupus flares, causing local skin and systemic inflammation and tissue injury, including the kidneys, through poorly understood mechanisms. To address this knowledge gap, we exposed asymptomatic, young female lupus-prone mice to UVB, inducing skin and kidney inflammation with proteinuria, accompanied by neutrophil infiltration in both organs and formation of neutrophil extracellular traps (NETs), known for their proinflammatory and immunogenic properties that drive lupus development. In both the skin and kidneys, infiltrated neutrophils expressed pro-inflammatory cytokines, complement C3, and CXCR4, a chemokine receptor facilitating immune cell transmigration between organs. When exposed in vitro to UVB or platelet-activating factor, a lipid mediator produced by UVB-irradiated keratinocytes, mouse neutrophils expressed cytokines/C3, which partially co-expressed with CXCR4, enabling them to exert proinflammatory and transmigratory effects. In a causality study, inhibiting CXCR4 significantly reduced neutrophil infiltration to the kidneys, resulting in ameliorated renal accumulation of NETs and NET-associated cytokines/C3, and decreased proteinuria, indicating a role of CXCR4 in the transmigration of neutrophils from the skin to kidneys in UVB-irradiated lupus-prone mice. Through a novel approach, we inhibited NETosis via nuclear envelope regulation in UVB-irradiated MRL/lpr·lmnB1Tg mice in which strengthening nuclear envelope integrity reduced NET formation, concomitantly decreasing exhibition of NET-associated cytokines/C3 in the skin and kidneys, thereby ameliorating proteinuria. Therefore, this study unveils a new mechanism by which NETosis drives UVB-triggered acute lupus flares, highlighting neutrophil transmigration and NET formation as potential therapeutic targets. Remarkably, nuclear envelope regulation holds significant potential for developing targeted therapies in lupus and other NETosis-related diseases. SIGNIFICANCE Sunlight overexposure triggers acute lupus flares through poorly understood mechanisms. NETosis is known important in lupus pathogenesis, but its contribution to UVB-induced lupus flares remains unexplored. UVB-irradiation triggered neutrophil infiltration and formation of NETs that exhibit cytokines/C3, leading to skin and kidney inflammation, and proteinuria in originally asymptomatic, young female lupus-prone mice. UVB-irradiation empowered skin neutrophils with proinflammatory and transmigratory capability, enabling them transmigration to the kidneys. Importantly, blocking renal neutrophil infiltration by CXCR4 inhibition, or inhibiting NETosis through a novel nuclear envelope regulation strategy, ameliorated UVB-induced acute lupus flares. These studies unveil a new mechanism linking sunlight exposure to lupus pathogenesis, emphasizing the importance of NETosis, and identifying neutrophil transmigration and NET formation as potential therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest.