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Study finds pathway for UVB light exposure as trigger for flares in SLE
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ATLANTA — Upregulation of the cGAS-STING pathway may be implicated in disease flares of systemic lupus erythematosus that are triggered by exposure to ultraviolet B light, according to a speaker at ACR/ARP 2019.
Sladjana Skopelja -Gardner, MD, of the University of Washington in Seattle, and colleagues, wanted to answer one key question: How does photosensitivity lead to disease flares in SLE? “Our hypothesis was that type I interferon response is the link from photosensitivity to disease flares,” she said. “Previous studies have alluded to this and shown that there is a link here.”
Theyevaluated the role of cyclic cGAS in UVB light-mediated skin injury. Skopelja-Gardner suggested that the cGAS-STING pathway can trigger expression of inflammatory genes.
The group created a mouse model to assess three other key research areas. One was to identify the magnitude of interferon response in the skin of mice, and whether there were differences between female and male mice. The next was to determine whether skin response was associated with systemic effects. The third was to elucidate the pathway of IFN response to UV light exposure.
The researchers exposed B6 female and male mice, along with female cGAS- and lfnar-deficient mice to a single, 500 mJ/cm2 dose of UVB light.
Blood draws and skin biopsies were performed at baseline and at several time points after exposures. Lab analyses then quantified ISG and inflammatory gene information.
Results showed that the single dose of light triggered a 10-fold increase in ISG expression at 6 and 48 hours after exposure. “We observed a more exaggerated response at 6 hours in female mice,” Skopelja-Gardner said. “Interferon response also persists for 48 hours.”
Importantly, significantly greater ISG upregulation was observed in female mice compared to age-matched male counterparts, according to Skopelja-Gardner. “All subsequent experiments should be done in female B6 mice,” she said.
Also at the 6-hour time point, local cutaneous interferon I response was accompanied by circulating “IFN-beta protein levels and upregulation of ISG expression in the peripheral blood cells,” according to Skopelja-Gardner.
No ISG expression was observed in female mice deficient in cGAS at 6 hours after light exposure. By 24 hours, a small amount of ISG expression was observed in the cGAS deficient mice, but the level was significantly lower than in the B6 control mice.
Also in mice with no cGAS, ISG expression in the peripheral blood cells was significantly reduced.
Conversely, TNF-alpha, IL-6, and IL-beta expression in the skin were unaffected by a lack of cGAS at 6 hours after exposure.
Skopelja-Gardner added that ISG expression in non-lesional skin that was covered during exposure was detected at both the 6- and 24-hour time points. ISG expression in these nonlesional areas was dependent on cGAS at 6 hours and partially dependent on cGAS at 24 hours.
“Acute skin exposure to UVB light triggers rapid and sustained ISG expression in both skin and blood,” the researchers concluded. “The requirement for cGAS in UVB light-mediated IFN-I response in the skin is temporally regulated. Presence of IFN-I signature in both the non-lesional skin as well as in peripheral blood cells, together with increased circulating IFN-beta levels, provide a model by which skin exposure to UVB light drives systemic activation of the IFN-I response.”
Skopelja-Gardner closed by raising and answering the key questions the group hoped to answer. “Does the cGAS-STING pathway contribute to inflammatory responses and production of cytokines? It does,” Skopelja-Gardner said. “Is cGAS necessary for interferon response in the blood? It is.” – by Rob Volansky
Reference:
Skopelja-Gardner S. Abstract #1762. UV light induces acute type I interferon production in the skin and blood which is cGAS dependent. Presented at: American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; Nov. 9-13, 2019; Atlanta.
Disclosure: Skopelja-Gardner reports no relevant financial disclosures.