The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
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eLife assessment
This study presents a useful assessment of the possible role of type I interferons in inhibiting Adam17 protease/sheddase activity and their correlation with decreased Langerhans Cells signature in lesional and nonlesional CLE and murine models as cause of photosensitive lupus. The data were collected and analyzed using a solid methodology. This work will be of interest to scientists interested in photosensitivity in the setting of lupus.
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Abstract
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.
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eLife assessment
This study presents a useful assessment of the possible role of type I interferons in inhibiting Adam17 protease/sheddase activity and their correlation with decreased Langerhans Cells signature in lesional and nonlesional CLE and murine models as cause of photosensitive lupus. The data were collected and analyzed using a solid methodology. This work will be of interest to scientists interested in photosensitivity in the setting of lupus.
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Reviewer #1 (Public Review):
This study demonstrates that Langerhans ADAM17 is lower in nonlesional skin and type I interferons have effects on ADAM17. ADAM17 releases EGFR ligands that preserve epidermal integrity. LC ROS is lower with high type I interferons, accompanied by reduced epidermal EGFR phosphorylation in nonlesional skin in SLE. The authors did an outstanding job with data from 3 animal models and human lupus skin to demonstrate their findings.
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Reviewer #2 (Public Review):
Many of the questions about type I interferon and photosensitivity have already been studied in murine lupus models but most importantly in skin biopsies from both lesional and non-lesional cutaneous lupus. The authors should try to link their data to the existing literature and validate their results by using human samples, as not all murine lupus models have a strong interferon-mediated disease. Other important aspects of the work include whether or not the authors have considered knocking out the mice for ADAM17 and reassessing the function of the Langerhans cells? Last but not least, some of the data presented will need to be validated by more in vitro work that will shed more light on the functional properties of ADAM17 in Langerhans cells and inflammatory response in cutaneous lupus.
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Reviewer #3 (Public Review):
The study by Li et al investigates the role of type I interferon in suppressing ADAM17-mediated release of EGFR, the pathway previously implicated by this group in photosensitive skin reactions. Understanding the relevance of lupus murine models to the human disease is very important and the studies address this important gap in the knowledge. The most significant findings are: 1) the same high IFN and low Langerhans cell (LC) signatures seen in a lupus patient's skin, exist in the non-lesional skin of lupus mouse models; 2) IFN-Is and IFN-I signaling suppress ADAM17 activity in LCs in vitro and in vivo; 3) Blocking IFN-I signaling ameliorates photosensitive reactions, in an EGFR-dependent manner. These three conclusions are largely supported by the presented evidence but could be distilled as well as …
Reviewer #3 (Public Review):
The study by Li et al investigates the role of type I interferon in suppressing ADAM17-mediated release of EGFR, the pathway previously implicated by this group in photosensitive skin reactions. Understanding the relevance of lupus murine models to the human disease is very important and the studies address this important gap in the knowledge. The most significant findings are: 1) the same high IFN and low Langerhans cell (LC) signatures seen in a lupus patient's skin, exist in the non-lesional skin of lupus mouse models; 2) IFN-Is and IFN-I signaling suppress ADAM17 activity in LCs in vitro and in vivo; 3) Blocking IFN-I signaling ameliorates photosensitive reactions, in an EGFR-dependent manner. These three conclusions are largely supported by the presented evidence but could be distilled as well as strengthened by additional data.
One of the strengths of the study is that the authors defined the relevance of lupus skin mouse models to human disease in the context of the Interferon-LC axis. The extensive computational approaches represent useful tools to compare cellular and molecular signatures across samples as well as species. This is highly relevant to the studies of lupus, a highly complex disease, for which the relevance of murine models has remained undefined. Major strengths related to the Aims of the study are that the authors established a role of interferon in suppressing Adam17 activity in the skin and showed that blocking interferon can reduce sunlight-induced skin inflammation in the lupus murine models. Interestingly, the authors observed that blocking IFN signaling in the absence of a high IFN-signature worsened sunlight-induced skin injury. The specificity of Adam17 in LCs for TNFR1 shedding provides an elegant approach to probing Adam17 activity in these cells.
While the three conclusions stated above are largely supported by the presented evidence, the data supporting a direct role of ADAM17 in IFN-triggered photosensitive reactions could be strengthened. Some of the concerns are outlined below:
(1) Computational analyses in Figures 1 and 2 emphasize the co-occurrence of a high IFN-I signature and a low LC and/or DC signatures. It is not clear if the downregulation of the DC gene set indicates diminished presence of LCs in the non-lesional skin of the lupus mouse models or "reflects decreased LC function" as the authors suggest.(2) Given the hypothesis that IFN-I may be the cause of a decreased DC signature in the mouse skin, it would be relevant to ask if this signature is also decreased in the IMQ model, which is a known model of IFN-induction as confirmed by the authors. Likewise, asking how anti-IFNAR treatment affects the DC signature / LC numbers would be important, in the absence and presence of UV. The authors indicate in Fig. 5I that IMQ reduces LC numbers.
(3) Decreased inflammation in LCad17 mice in the IMQ+UV model is unexpected. Previous studies by this group showed increased UV-induced inflammation in the absence of LC-ADAM17 (Shipman et al 2018). Therefore, it is not surprising that anti-IFNAR did not have an impact in these mice as ADAM17 deficiency appears to have normalized the response. These results are not addressed in the context of the previously published findings.
(4) Including the data that demonstrate the specificity of LCs for Adam17 expression in the epidermis and shedding of TNFR1 as a readout of LC-ADAM17-specific activity in the main figures would be important.
(5) UV light is an important inducer of IFN. Authors have previously shown that UV also induces Adam17 expression. Therefore, the question remains whether a high baseline IFN signature in lupus skin suppresses UV-induced Adam17 expression?
(6) A direct mechanistic link between high IFN-I and loss of Adam17 activity driving photosensitive reactions could be strengthened. Would blocking Adam17 with a blocking antibody suppress photosensitive reactions in lupus mouse models? Would treating LCAd17 mice with IFN fail to enhance or diminish UV-induced inflammation?
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