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bioRxiv · 10.1101/2023.12.23.572573

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

Lyu, X.·Li, M.·Zhang, P. L.·Wei, W.·Werth, V. P.·Liu, M.-L.
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Abstract

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.

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Lyu, X., Li, M., Zhang, P. L., Wei, W., Werth, V. P., Liu, M.-L.. 2023-12-23. Neutrophil extracellular traps drive lupus flares with acute skin and kidney inflammation triggered by ultraviolet irradiation. https://doi.org/10.1101/2023.12.23.572573

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