Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1
IntroductionUltraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is in...
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| Format: | Article |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1384606/full |
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| author | Shannon N. Loftus Shannon N. Loftus Mehrnaz Gharaee-Kermani Mehrnaz Gharaee-Kermani Bin Xu Tyson M. Moore Andrew Hannoudi Mischa J. Mallbris Benjamin Klein Johann E. Gudjonsson J. Michelle Kahlenberg J. Michelle Kahlenberg |
| author_facet | Shannon N. Loftus Shannon N. Loftus Mehrnaz Gharaee-Kermani Mehrnaz Gharaee-Kermani Bin Xu Tyson M. Moore Andrew Hannoudi Mischa J. Mallbris Benjamin Klein Johann E. Gudjonsson J. Michelle Kahlenberg J. Michelle Kahlenberg |
| author_sort | Shannon N. Loftus |
| collection | DOAJ |
| description | IntroductionUltraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown.MethodsHere, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress Ifnk in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure.ResultsWe identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. In vivo, overexpression of epidermal Ifnk resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1).DiscussionThese data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB. |
| first_indexed | 2024-04-24T11:35:59Z |
| format | Article |
| id | doaj.art-2688932f602c4078829249e84a14bb01 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T11:35:59Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2688932f602c4078829249e84a14bb012024-04-10T05:05:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13846061384606Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1Shannon N. Loftus0Shannon N. Loftus1Mehrnaz Gharaee-Kermani2Mehrnaz Gharaee-Kermani3Bin Xu4Tyson M. Moore5Andrew Hannoudi6Mischa J. Mallbris7Benjamin Klein8Johann E. Gudjonsson9J. Michelle Kahlenberg10J. Michelle Kahlenberg11Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesGraduate Program in Immunology, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDepartment of Dermatology, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDepartment of Dermatology, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDepartment of Dermatology, University of Michigan, Ann Arbor, MI, United StatesIntroductionUltraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown.MethodsHere, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress Ifnk in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure.ResultsWe identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. In vivo, overexpression of epidermal Ifnk resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1).DiscussionThese data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1384606/fullinterferonapoptosisultraviolet lightkeratinocytelupus |
| spellingShingle | Shannon N. Loftus Shannon N. Loftus Mehrnaz Gharaee-Kermani Mehrnaz Gharaee-Kermani Bin Xu Tyson M. Moore Andrew Hannoudi Mischa J. Mallbris Benjamin Klein Johann E. Gudjonsson J. Michelle Kahlenberg J. Michelle Kahlenberg Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 Frontiers in Immunology interferon apoptosis ultraviolet light keratinocyte lupus |
| title | Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| title_full | Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| title_fullStr | Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| title_full_unstemmed | Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| title_short | Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| title_sort | interferon alpha promotes caspase 8 dependent ultraviolet light mediated keratinocyte apoptosis via interferon regulatory factor 1 |
| topic | interferon apoptosis ultraviolet light keratinocyte lupus |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1384606/full |
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