Neutrophil extracellular traps drive lupus flares with acute skin and kidney inflammation triggered by ultraviolet irradiation
Neutrophil extracellular traps (NETs) are major pathogenic effectors in chronic systemic lupus erythematosus (SLE) pathogenesis, but how they mediate acute, UVB-triggered skin inflammation and subsequent systemic injury remains poorly defined. Using UVB-irradiated lupus-prone mice, we identified an acute NETosis-driven skin-kidney inflammatory axis linking photosensitivity to renal inflammation. UVB induced concurrent skin and kidney inflammation with neutrophil infiltration, NETosis, and release of NET-associated effector cytokines/complement C3 and proteinuria. Mechanistically, PKC-dependent nuclear envelope rupture licensed NETosis, whereas Pkc deletion markedly suppressed NET formation and inflammation in both organs. Interestingly, only a subset of skin-infiltrating neutrophils underwent local NETosis. Spatiotemporal photoconversion tracking revealed that surviving, CXCR4-expressing neutrophils disseminated from UVB-irradiated skin to kidneys, where they underwent secondary NETosis, delivering cytokines/C3 to drive renal inflammation. Genetic or pharmacological CXCR4 inhibition blocked this dissemination, attenuating renal inflammation and proteinuria. These findings identify an acute NETosis-driven skin-kidney axis, highlighting PKC-dependent NETosis and CXCR4-mediated neutrophil dissemination as therapeutic targets in photosensitive lupus.