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

Sunlight triggers lupus flares causing both local skin and systemic inflammation, including lupus nephritis, through poorly understood mechanisms. To address this knowledge gap, we found that UVB irradiation of asymptomatic, young female lupus-prone mice induced skin and kidney inflammation with proteinuria, accompanied by neutrophil infiltration and neutrophil extracellular trap (NET) formation. Furthermore, UVB irradiation induced co-expression of CXCR4 and cytokines/C3 by neutrophils in vitro and in vivo, in the skin and kidneys of lupus-prone mice, indicating their transmigratory and pro-inflammatory potentials. A causality study demonstrated that inhibiting CXCR4 attenuated renal neutrophil infiltration, accumulation of NETs, NET-associated cytokines/C3, and proteinuria in UVB-irradiated lupus-prone mice. Remarkably, inhibiting NETosis through a novel strategy targeting nuclear envelope integrity reduced deposition of NET-associated cytokines/C3 in skin and kidneys, attenuating proteinuria in UVB-irradiated MRL/lpr·lmnB1 Tg mice. Our investigation unveils a new mechanism by which neutrophil NETs drive the early onset of lupus flares triggered by UVB-irradiation. Targeting neutrophil transmigration and NETosis could be promising therapeutic strategies.