Biology subjects

Werth, V. P.

Publications and source records attributed to Werth, V. P..

3 recordsLinked to original sources

bioRxiv2025

Keratinocyte VISTA attenuates UV light-induced skin injury by suppressing cutaneous type I interferon (IFN-I) response

Persistent production of type I interferons (IFN-Is) is a hallmark of cutaneous lupus erythematosus (CLE). Ultraviolet (UV) light stimulates IFN-I response in the skin and exacerbates CLE. Here, we identify V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) as a negative regulator of both basal and UV-induced IFN-I responses in the skin and show that VISTA limits skin photosensitivity in an IFN-I- dependent manner, in part through Stimulator of Interferon Genes (STING). Furthermore, we demonstrate a novel role for VISTA in keratinocytes both at steady state and in response to UV light. Conditional deletion of VISTA in epidermal keratinocytes results in >10-fold increase in the basal skin IFN-I score and a heightened UV-induced skin injury score, which is dependent on IFN-I signaling. VISTA-targeting monoclonal antibodies suppress UV-induced IFN-I response in human keratinocytes and in mice expressing human VISTA in vivo, which also reduces UV-induced skin injury score. Our findings highlight VISTA as a potential therapeutic target for suppressing IFN-I responses in cutaneous lupus patients who suffer from UV-induced skin inflammation.

immunology↗

bioRxiv2023

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.

pathology↗

bioRxiv2019

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent.

Most systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.

immunology↗