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; Kawasumi, Masaoki; Green, Richard; Gale, Michael; Kalus, Andrea; Werth, Victoria P.; Elkon, Keith B.

doi:10.1101/835132

Cited by 14 publications

(25 citation statements)

References 80 publications

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“…Moreover, studies have proposed that UVR could also induce type I IFNs via nucleic acid-damage and induction of damageassociated 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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“…Moreover, in vitro- and animal studies have proposed that UVR could also induce type I interferons via nucleic acid-damage and induction of damage associated molecular patterns (DAMPs) that can be sensed by toll-like receptors and the stimulator of interferon genes (STING) (53, 54). Interestingly, type I interferons were also shown to be induced in the skin of healthy human individuals upon UVR exposure, which lines up with the results from this study (55). If the type I interferon-pathway was indeed regulated by UVR, this could provide a link between MS and Lupus.…”

Section: Discussionsupporting

confidence: 90%

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Ostkamp¹,

Salmen

Pignolet

et al. 2020

Preprint

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Background: 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 disease severity, the mechanisms of action, and effect-modification by medication and sun-sensitivity associated MC1R variants. Methods: Two multi-center cohort studies (nNationMS=946, nBIONAT=991). Outcomes were the multiple sclerosis severity score (MSSS) and the number of Gd-enhancing lesion (GELs). RNAseq of four immune cell populations before and after UV-phototherapy of five MS patients. Results: High serum vitD was associated with reduced MSSS (PNationMS=0.021; PBIONAT=0.007) and reduced risk for disease aggravation (PNationMS=0.032). Low latitude was associated with higher vitD, lower MSSS (PNationMS=0.018), fewer GELs (PNationMS=0.030) and reduced risk for aggravation (PNationMS=0.044). The influence of latitude on disability seemed to be lacking in the subgroup of interferon-β treated patients (interaction-PBIONAT=0.042, interaction-PNationMS=0.053). In genetic analyses, carriers of MC1R:rs1805008(T), who reported increased sensitivity towards sunlight (PNationMS=0.038), the relationship between latitude und the number of GELs was inversed (PNationMS=0.001). Phototherapy induced a vitD and type I interferon signature that was most apparent in the transcriptome of monocytes (P=1x10-6). Conclusion: VitD is associated with reduced MS severity and disease aggravation. This is likely driven by sun-exposure, as latitude also correlated with disability and serum vitD. However, sun-exposure might be detrimental for sun-sensitive patients. A direct induction of type I interferons through sun-exposure could explain a reduced effect of latitude in interferon-β treated patients. This could also explain opposite effects of sun-exposure in MS and the type I interferon and sun-sensitivity-associated disease Lupus.

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“…Moreover, mRNA measurements do not formally evaluate type I IFN signaling, as transcription is not necessarily associated with translation 190,191 . Immunostaining based on type I IFN-specific antibodies coupled with immunohistochemistry or immunofluorescence microscopy has also been successfully employed to detect type I IFN in bioptic specimens from cancer patients and mice [192][193][194][195][196][197][198] . However, it is complex to discriminate between intracellular expression and secretion on these technical platforms.…”

Section: Monitoring the Release Of Type I Ifnsmentioning

confidence: 99%

Detection of immunogenic cell death and its relevance for cancer therapy

et al. 2020

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Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

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

Cited by 14 publications

References 80 publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Detection of immunogenic cell death and its relevance for cancer therapy

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