期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 142, 期 3 PT A, 页码 633-+出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2021.04.037
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资金
- Deutsche Forschungsgemeinschaft (German Research Foundation, Bonn, Germany) [TRR237 369799452/404458960, KFO 249/GU1212/1-1, KFO 249/GU1212/1-2, KFO 249/LE1074/4-2, CRC237 369799452/B21]
- Medical Faculty, TU Dresden (Dresden, Germany)
- Roche
The exonuclease TREX1 plays a protective role in preventing DNA accumulation and innate immune activation. TREX1 mutations lead to chronic DNA damage, IFN-1 response, and associated diseases such as Aicardi-Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus. Patients with lupus and TREX1 mutation show enhanced photosensitivity and increased levels of DNA damage in response to UV radiation, which can trigger disease flares.
The exonuclease TREX1 safeguards the cells against DNA accumulation in the cytosol and thereby prevents innate immune activation and autoimmunity. TREX1 mutations lead to chronic DNA damage and cell-intrinsic IFN-1 response. Associated disease phenotypes include Aicardi.Goutie` res syndrome, familial chilblain lupus, and systemic lupus erythematosus. Given the role of UV light in lupus pathogenesis, we assessed sensitivity to UV light in patients with lupus and TREX1 mutation by phototesting, which revealed enhanced photosensitivity. TREX1-deficient fibroblasts and keratinocytes generated increased levels of ROS in response to UV irradiation as well as increased levels of 8-oxo-guanine lesions after oxidative stress. Likewise, the primary UV-induced DNA lesions cyclobutane pyrimidine dimers were induced more strongly in TREX1-deficient cells. Further analysis revealed that single-stranded DNA regions, frequently formed during DNA replication and repair, promote cyclobutane pyrimidine dimer formation. Together, this resulted in a strong UV-induced DNA damage response that was associated with a cGAS-dependent IFN-1 activation. In conclusion, these findings link chronic DNA damage to photosensitivity and IFN-1 production in TREX1 deficiency and explain the induction of disease flares on UV exposure in patients with lupus and TREX1 mutation.
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