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

Skopelja-Gardner, Sladjana; An, Jie; Tai, Joyce; Tanaka, Lena; Sun, Xizhang; Hermanson, Payton; Baum, Rebecca; Kawasumi, Masaoki; Green, Richard; Gale, Michael; Kalus, Andrea; Werth, Victoria P.; Elkon, Keith B.

doi:10.1038/s41598-020-64865-w

Cited by 71 publications

(50 citation statements)

References 79 publications

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“…Moreover, studies have proposed that UVR could also induce type I IFNs via nucleic acid-damage and induction of damage-associated molecular patterns that can be sensed by Toll-like receptors and the stimulator of IFN genes ( 54 , 55 ). Interestingly, type I IFNs were also shown to be induced in the skin of healthy human individuals upon UVR exposure, which is in lines with the results from this study ( 56 ). If the type I IFN pathway was indeed regulated by UVR, this could provide a link between MS and lupus.…”

Section: Discussionsupporting

confidence: 91%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Görlich³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β–treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

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Section: Discussionsupporting

confidence: 91%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Görlich³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…DNAse II-deficient mice provide another example of excessive DNA accrual leading to the activation of multiple nucleic acid sensing pathways since the cGAS-STING, AIM2, and endosomal TLRs all have been shown to contribute to the development of autoimmunity or autoinflammation in this model ( 16 , 55 , 56 ). It is also possible that different DNA sensors may function in tissue specific manner for instance cGAS STING pathway can still contribute to certain aspects of disease such as the cutaneous lupus features as suggested by Skopelja-Gardner et al ( 20 ). A better understanding of the interplay between cells responding to endogenous nucleic acid ligands will provide important insights for preventing the onset and progression of both autoinflammatory and autoimmune diseases in patients suffering from these conditions.…”

Section: Discussionmentioning

confidence: 99%

“…cGAMP, the cyclic dinucleotide generated by cGAS that activates STING, has been shown to be modestly elevated in the serum of a limited number of SLE patients ( 19 ). Most recently, UVB exposure which can drive lupus flares leads to an elevated type I IFN-I gene signature in the skin of mice which is dependent on the cGAS pathway and enhanced when cGAMP hydrolysis is blocked ( 20 ). Elevated STING activity has further been associated with increased expression of type I IFNs and ISGs ( 21 , 22 ) and the degradation of damaged mitochondrial DNA by autophagy in patient populations ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

et al. 2021

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Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGASKOFaslpr mice on a pure MRL/Faslpr background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity.

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“…Skin moisture levels can alter immune expression of antimicrobial proteins [ 76 ] as well as immune cell infiltration [ 79 ]. UV exposure can promote wound closure [ 84 ], as well as interferon signature [ 83 ]. Time of day can alter fibroblast activity in the wound [ 85 ], as well as immune cell trafficking [ 86 ].…”

Section: Environmental Effects: the Outside World Alters The Cutanmentioning

confidence: 99%

“…However, UV radiation also has well documented effects on human immune responses and appears to be a double-edged sword in the wound immune response. UV radiation of B wavelength only needs one dose to actively induce murine skin to produce type I interferon, as well a number of distinct antiviral genes including interferon regulatory transcription factor 7 (Irf7), interferon induced protein with tetratricopeptide repeats 1 (Ifit1), interferon stimulated gene 15 (Isg15), and myxovirus resistance 1 (Mx1) [ 83 ]. Induction of these genes can possibly confer a protective, antiviral state to the immune microenvironment.…”

Section: Environmental Effects: the Outside World Alters The Cutanmentioning

confidence: 99%

The Cutaneous Wound Innate Immunological Microenvironment

Kirchner

Lei

MacLeod

2020

IJMS

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The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

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

Cited by 71 publications

References 79 publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

The Cutaneous Wound Innate Immunological Microenvironment

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