Neutrophil Cytokines and NETs Mediate Skin and Kidney Inflammation in Lupus Flare Under UVB Irradiation
Journal of Investigative Dermatology
Ultraviolet B (UVB) triggers lupus flare by worsening skin lesions and systemic symptoms, i.e. lupus nephritis. We have reported that UVB exposure induces skin inflammation with neutrophil infiltration and neutrophil extracellular trap (NET) formation in mice. We also found that UVB exposure induced lupus flare with skin inflammation and proteinuria in young female lupus-prone mice. The relevant mechanisms regarding dermal-renal crosstalk in lupus flare is unclear. We examined skin lesions, proteinuria, infiltration of neutrophils, their expression of cytokines or complement C3, and NETosis in skin and kidneys of UVB-irradiated MRL/lpr mice. UVB induced inflammatory responses in skin and kidneys with proteinuria, elevated skin thickness, immune cell infiltration, increased NETosis, and deposition of NET-associated IFNα or C3 both in skin and kidneys. Infiltrated cells in skin are positively correlated with proteinuria (r=0.57, p<0.05), suggesting a link between skin infiltrates and kidney injury. In kidneys, glomerular hypercellularity, CXCR4-positive neutrophils, NETs, NET-associated IFNα or C3 deposition, correlated with proteinuria in UVB-irradiated lupus mice. In vitro, UVB or platelet-activating factor upregulated IFNα and C3 expression in mouse neutrophils, and portion of them coexpress CXCR4, which may be a mediator for neutrophil transmigration between skin and kidneys. Intraperitoneal application of CXCR4 inhibitor IT1t significantly attenuated proteinuria, with reduced CXCR4-positive neutrophils and NET-associated IFNα (3.2% vs 0.43% Area in UVB vs IT1t+UVB mice, P<0.01) in kidneys of UVB-irradiated MRL/lpr mice. Furthermore, overexpression of nuclear lamin B attenuated NETosis and NET-associated IFNα and C3 in kidneys of UVB-irradiated MRL/lpr-lmnb1Tg mice. NET-associated IFNα (r=0.49, p<0.01) or C3 (r=0.38, p<0.05) were correlated with proteinuria. Thus, inhibition of CXCR4-mediated transmigration or neutrophil NETosis ameliorated UVB-triggered lupus flare in skin and kidneys.
Lyu X, Li M, Zhang P, Wei W, Werth VP, Liu M. Neutrophil cytokines and NETs mediate skin and kidney inflammation in lupus flare under UVB irradiation. J Invest Dermatol. 2023 May;143(5 Suppl.):S200. doi:10.1016/j.jid.2023.03.1181