Background/Purpose: Ultraviolet B (UVB) exposure triggers lupus flare by worsening skin lesions and systemic symptoms such as lupus nephritis. The effects of UVB-induced skin inflammation on kidney activity have not been well understood. NETosis has been implicated in lupus. We have seen that UVB induces neutrophil recruitment to skin with NET formation and exhibition of NET-associated proinflammatory cytokines. Our mechanistic studies revealed that nuclear envelope rupture and NET formation are driven by PKCα-mediated lamin B (lmnb) disassembly. Strengthening nuclear envelope by lamin B overexpression decreases NETosis and exhibition of NET-associated cytokines in the skin of UVB-irradiated lmnb1^Tg/+ mice. Furthermore, other studies reported that UVB can trigger an IFNα signature both in skin and kidneys, and neutrophils in the inflamed skin can migrate back to the circulation through reverse transmigration, then be recruited to the kidneys, resulting in transient proteinuria in wildtype mice. However, the involvement of NETosis in UVB-mediated lupus flare in skin and kidneys has not been studied.

Methods: We generated lupus-prone mice with lamin B overexpression by backcrossing lmnb1^Tg/+ mice with MRL/lpr (lpr) mice for 10 generations. Female MRL/lpr-lmnb1^Tg/+ mice and their MRL/lpr littermates (8-week-old) were exposed to UVB at 150 mJ/cm²/day for 5 consecutive days. We examined skin lesions, proteinuria, infiltrates, and NET formation in the skin and kidneys of these mice.

Results: Our data show that UVB exposure induces inflammatory responses with increased skin thickness, more infiltrates and NET formation in the skin, proteinuria and increased NET formation, NET-associated IFNα, IgG deposition, and hypercellularity in the kidneys of UVB-irradiated MRL/lpr mice. In addition, our data demonstrate decreased NET formation and less skin inflammation with attenuated skin thickness and infiltrates (p< 0.01) in the skin, decreased proteinuria, and reduced NET formation, NET-associated IFNα, IgG deposition, and hypercellularity in the kidneys of MRL/lpr-lmnb1^Tg/+ mice as compared to those in control MRL/lpr mice after UVB exposure. Interestingly, the skin infiltrates (r=0.57, p< 0.05) or NET formation in skin (r=0.54, p< 0.05) were positively correlated with proteinuria. Importantly, NET formation (r=0.56, p< 0.05), NET-associated IFNα (r=0.60, p< 0.05), IgG deposition (r=0.7, p< 0.01), or hypercellularity (r=0.65, p< 0.01) in glomeruli were also positively correlated with proteinuria.

Conclusion: We conclude that inhibition of NET formation by strengthening the nuclear envelope integrity can ameliorate UVB-triggered skin inflammation, proteinuria, and kidney damage in young lupus-prone mice. Therefore, our results provide insights into novel therapeutics into UVB-induced lupus flare.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/strengthening-nuclear-envelope-ameliorates-uvb-triggered-skin-inflammation-and-kidney-damage-in-lupus-mice/