Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

Mrinal K. Sarkar; Grace A. Hile; Lam C. Tsoi; Xianying Xing; Jianhua Liu; Yun Liang; Celine C. Berthier; William R. Swindell; Matthew T. Patrick; Shuai Shao; Pei Suen Tsou; Ranjitha Uppala; Maria A. Beamer; Anshika Srivastava; Stephanie L. Bielas; Paul W. Harms; Spiro Getsios; James T. Elder; John J. Voorhees; Johann E. Gudjonsson; J. Michelle Kahlenberg

doi:10.1136/annrheumdis-2018-213197

Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

Mrinal K. Sarkar, Grace A. Hile, Lam C. Tsoi, Xianying Xing, Jianhua Liu, Yun Liang, Celine C. Berthier, William R. Swindell, Matthew T. Patrick, Shuai Shao, Pei Suen Tsou, Ranjitha Uppala, Maria A. Beamer, Anshika Srivastava, Stephanie L. Bielas, Paul W. Harms, Spiro Getsios, James T. Elder, John J. Voorhees, Johann E. GudjonssonJ. Michelle Kahlenberg

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146 Scopus citations

Abstract

Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10 -04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

Original language	English (US)
Pages (from-to)	1653-1664
Number of pages	12
Journal	Annals of the Rheumatic Diseases
Volume	77
Issue number	11
DOIs	https://doi.org/10.1136/annrheumdis-2018-213197
State	Published - Nov 1 2018
Externally published	Yes

Keywords

autoimmune diseases
cytokines
inflammation

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
General Biochemistry, Genetics and Molecular Biology

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10.1136/annrheumdis-2018-213197

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Sarkar, M. K., Hile, G. A., Tsoi, L. C., Xing, X., Liu, J., Liang, Y., Berthier, C. C., Swindell, W. R., Patrick, M. T., Shao, S., Tsou, P. S., Uppala, R., Beamer, M. A., Srivastava, A., Bielas, S. L., Harms, P. W., Getsios, S., Elder, J. T., Voorhees, J. J., ... Kahlenberg, J. M. (2018). Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Annals of the Rheumatic Diseases, 77(11), 1653-1664. https://doi.org/10.1136/annrheumdis-2018-213197

Sarkar, MK, Hile, GA, Tsoi, LC, Xing, X, Liu, J, Liang, Y, Berthier, CC, Swindell, WR, Patrick, MT, Shao, S, Tsou, PS, Uppala, R, Beamer, MA, Srivastava, A, Bielas, SL, Harms, PW, Getsios, S, Elder, JT, Voorhees, JJ, Gudjonsson, JE & Kahlenberg, JM 2018, 'Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa', Annals of the Rheumatic Diseases, vol. 77, no. 11, pp. 1653-1664. https://doi.org/10.1136/annrheumdis-2018-213197

@article{606879c397614f8db964bc2ff8bab676,

title = "Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa",

abstract = "Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10 -04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.",

keywords = "autoimmune diseases, cytokines, inflammation",

author = "Sarkar, {Mrinal K.} and Hile, {Grace A.} and Tsoi, {Lam C.} and Xianying Xing and Jianhua Liu and Yun Liang and Berthier, {Celine C.} and Swindell, {William R.} and Patrick, {Matthew T.} and Shuai Shao and Tsou, {Pei Suen} and Ranjitha Uppala and Beamer, {Maria A.} and Anshika Srivastava and Bielas, {Stephanie L.} and Harms, {Paul W.} and Spiro Getsios and Elder, {James T.} and Voorhees, {John J.} and Gudjonsson, {Johann E.} and Kahlenberg, {J. Michelle}",

note = "Publisher Copyright: {\textcopyright} {\textcopyright} Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2018",

month = nov,

day = "1",

doi = "10.1136/annrheumdis-2018-213197",

language = "English (US)",

volume = "77",

pages = "1653--1664",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "11",

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TY - JOUR

T1 - Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

AU - Sarkar, Mrinal K.

AU - Hile, Grace A.

AU - Tsoi, Lam C.

AU - Xing, Xianying

AU - Liu, Jianhua

AU - Liang, Yun

AU - Berthier, Celine C.

AU - Swindell, William R.

AU - Patrick, Matthew T.

AU - Shao, Shuai

AU - Tsou, Pei Suen

AU - Uppala, Ranjitha

AU - Beamer, Maria A.

AU - Srivastava, Anshika

AU - Bielas, Stephanie L.

AU - Harms, Paul W.

AU - Getsios, Spiro

AU - Elder, James T.

AU - Voorhees, John J.

AU - Gudjonsson, Johann E.

AU - Kahlenberg, J. Michelle

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10 -04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

AB - Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10 -04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.

KW - autoimmune diseases

KW - cytokines

KW - inflammation

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U2 - 10.1136/annrheumdis-2018-213197

DO - 10.1136/annrheumdis-2018-213197

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SN - 0003-4967

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JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 11

ER -

Photosensitivity and type i IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

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