Type I Interferon Induction in Cutaneous DNA Damage Syndromes

Abstract

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression

“…The draining lymph nodes were harvested from panels of mice after exposure to UVB and single-cell suspensions were prepared after digestion according to the published protocol [40]. Cells were stained for CD4, CD25, Foxp3, IL-10, TGFβ and analyzed using a flow cytometer (Attune NxT, Thermofisher Scientific, Waltham MA, USA) as described [25], and the analysis was performed using FlowJo software version 10.6.1.…”

“…A single exposure to UVB light triggers an early cutaneous IFN-1 response exaggerated in mice and humans. UVB light stimulated not only a local but also a systemic IFN-1 response in the blood and kidneys [24,25].…”

Current concepts of photosensitivity in cutaneous lupus erythematosus

“…Subsequently, signaling of cGAMP via interferon regulatory factor (IRF) 3 leads to the release of proinflammatory cytokines ( 71 ). The release of type I IFN after DNA damage has been described in different cutaneous DNA damage syndromes ( 74 ). Also in lupus, the effects of UV irradiation on type I IFN activation has been investigated.…”

DNA double-strand breaks in immunoinflammatory rheumatic diseases

“…Один из самых тяжелых типов повреждения ДНК -ДР ДНК. Нарушения в системе РРП ДНК приводят к накоплению цитозольных одноцепочечных и двухцепочечных ДНК, которые могут действовать как мощные иммуностимуляторы посредством активации продукции интерферона I типа, влияя на процессы врожденного иммунного ответа [24]. Стабильность и сохранение генетической информации -основная задача функционирования клетки; любое повреждение ДНК сопровождается продукцией широкого спектра цитокинов, передающих информацию о повреждении, что приводит к остановке клеточного деления и развитию ответа на повреждение [25].…”