Background/Purpose: Ultraviolet B (UVB) exposure triggers lupus flare by worsening both skin lesions and systemic symptoms, i.e. lupus nephritis. We recently reported that UVB exposure induces skin inflammation with infiltration of neutrophils, which can form neutrophil extracellular traps (NETs) in wild-type mice. Interestingly, we recently found that UVB exposure of asymptomatic MRL-lpr lupus-prone mice induced lupus flare with not only skin inflammation, but also proteinuria. However, the underlying mechanisms remain unclear.

Methods: To study the relevant mechanisms, we investigated skin lesions, proteinuria, infiltrated neutrophils, their expression of cytokines or complement C3, and formation of NETs in both skin and kidneys of UVB-irradiated asymptomatic young female MRL-lpr lupus-prone mice.

Results: UVB exposure induced inflammatory responses in skin and kidneys with proteinuria, showing elevated skin thickness, immune cell infiltration, increased CXCR4 expression in neutrophils, and deposition of NETs, and NET-associated IFNα or C3 in both skin and kidneys. Interestingly, infiltrated cell count in skin was positively correlated with proteinuria (r=0.57, p< 0.05), indicating a link between skin infiltrates and kidney injury. In kidneys, glomerular hypercellularity (r=0.73, p< 0.05), CXCR4-positive neutrophils (r=0.7, p< 0.05), NETs (r=0.74, p< 0.05), NET-associated IFNα (r=0.81, p< 0.05) or C3 (r=0.88, p< 0.01) were correlated with proteinuria in UVB-irradiated lupus-prone mice, suggesting a role for CXCR4-positive neutrophils, NETs and their associated IFNα or C3 in kidney inflammation. To explore the origin of the proinflammatory neutrophils, we found that stimulation with UVB or platelet-activating factor can upregulate expression of CXCR4, IFNα or C3 in vitro in neutrophils from lupus-prone mice. About 20-50% of them co-expressed IFNα or C3 with CXCR4, which may mediate cross-organ communication. Given that only a portion of infiltrated neutrophils become NETotic in the skin of UVB-irradiated wildtype mice in our recent publication, we sought to explore if inhibition of CXCR4 can reduce kidney injury. Notably, intraperitoneal application of CXCR4 inhibitor IT1t significantly attenuated proteinuria, with reduced glomerular infiltration of CXCR4-positive neutrophils. Consequently, we found decreased glomerular deposition of neutrophil NETs and NET-associated IFNα (3.2% Area in UVB vs 0.43% in IT1t+UVB mice, P< 0.01) in kidneys of UVB-irradiated MRL/lpr mice with IT1t application as compared to those in mice without IT1t administration.

Conclusion: In conclusion, UVB-induced proinflammatory neutrophils and NETs contribute to skin and kidney inflammation during lupus flare in asymptomatic lupus-prone mice irradiated by UVB. Inhibition of CXCR4-mediated neutrophil transmigration ameliorated kidney inflammation with attenuated proteinuria in UVB-triggered lupus flare. Our results provide insights into novel therapeutics into UVB-induced lupus flare.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proinflammatory-neutrophils-and-nets-mediate-skin-and-kidney-inflammation-during-lupus-flare-in-asymptomatic-lupus-prone-mice-triggered-by-uvb/