Cutaneous lupus erythematosus (CLE) has a specific microRNA expression profile. MiR-885-5p
has been found to be downregulated in the epidermis of CLE lesions; however, its biological
role in the disease has not been studied. In this study, we show that miR-885-5p is
markedly reduced in CLE keratinocytes (KCs) with IFN-α and UVB being strong miR-885-5p
regulators in vitro. Microarray expression profiling of anti‒miR-885-5p‒transfected KCs identified PSMB5
as a direct target. Specific inhibition of miR-885-5p increased epidermal proliferation by modulating keratin
16 gene K16, BIRC5, TP63, and CDK4 proliferative genes and promoted NF-κB signaling pathway in human primary KCs by
increasing IκBα degradation. Silencing PSMB5 rescued the effect of miR-885-5p inhibition,
indicating that miR-885-5p regulates proliferation and NF-κB activation by targeting
PSMB5 in KCs. In addition, inhibition of miR-885-5p increased the ability of KCs to
attract leukocytes in a PSMB5-independent manner. We identified TRAF1 as another direct
target, and its silencing reduced leukocyte migration. Collectively, our findings
suggest that UVB and IFN-ɑ downregulate miR-885-5p in CLE KCs, leading to epidermal
inflammation by NF-κB activity enhancement and proliferation through PSMB5 and immune
recruitment through TRAF1. Our data indicate that miR-885-5p is a potential therapeutic
target in CLE.
Graphical abstract
Graphical Abstract
Abbreviations:
CLE (cutaneous lupus erythematosus), DEG (differentially expressed gene), DLE (discoid lupus erythematosus), HEKa (human epidermal keratinocyte), KC (keratinocyte), LNA (locked nucleic acid), miRNA (microRNA), SCLE (subacute cutaneous lupus erythematosus), siRNA (small interfering RNA)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Investigative DermatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells.Nat Protoc. 2010; 5: 371-382
- Pathophysiology of cutaneous lupus erythematosus.Arthritis Res Ther. 2015; 17: 182
- MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival.Cell Death Differ. 2011; 18: 974-984
- The functions of animal microRNAs.Nature. 2004; 431: 350-355
- The impact of microRNAs on protein output.Nature. 2008; 455: 64-71
- Molecular profiling of cutaneous lupus lesions identifies subgroups distinct from clinical phenotypes.J Clin Med. 2019; 8: 1244
- Ubiquitin signalling in the NF-kappaB pathway.Nat Cell Biol. 2005; 7: 758-765
- Immunohistochemical detection of proliferation and differentiation in discoid lupus erythematosus.J Am Acad Dermatol. 1991; 25: 1032-1038
- MicroRNAs in several cutaneous autoimmune diseases: psoriasis, cutaneous lupus erythematosus and atopic dermatitis.Cells. 2020; 9: 2656
- Distinctive cutaneous subsets in the spectrum of lupus erythematosus.J Am Acad Dermatol. 1981; 4: 471-475
- Cutaneous lupus erythematosus: an update.Indian Dermatol Online J. 2014; 5: 7-13
- Alopecia areata lesions show significant changes in immune and keratin biomarkers that correlate with cliical improvement with oral Janus kinase inhibitors PF-06651600 (JAK3) and PF-06700841 (TYK2/JAK1).J Invest Dermatol. 2019; 544 (139:S94)
- Basic Medical Research Award. The ubiquitin system.Nat Med. 2000; 6: 1073-1081
- Delineating the healthy human skin UV response and early induction of interferon pathway in cutaneous lupus erythematosus.J Invest Dermatol. 2019; 139: 2058-2061.e4
- NF-kB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation.Life Sci Alliance. 2021; 4e202000956
- TRAF molecules in inflammation and inflammatory diseases.Curr Pharmacol Rep. 2018; 4: 64-90
- miR-885-5p suppresses osteosarcoma proliferation, migration and invasion through regulation of β-catenin.Oncol Lett. 2019; 17: 1996-2004
- Cutaneous lupus erythematosus: diagnosis and treatment.Best Pract Res Clin Rheumatol. 2013; 27: 391-404
- An update on the pathogenesis of cutaneous lupus erythematosus and its role in clinical practice.Curr Rheumatol Rep. 2020; 22: 69
- Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.Ann Rheum Dis. 2018; 77: 1653-1664
- MicroRNA expression profiling identifies miR-31 and miR-485-3p as regulators in the pathogenesis of discoid cutaneous lupus.J Invest Dermatol. 2019; 139: 51-61
- Microarray study reveals a transforming growth factor-β-dependent mechanism of fibrosis in discoid lupus erythematosus.Br J Dermatol. 2016; 175: 302-313
- MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.PLoS One. 2007; 2e610
- miR-885-5p upregulation promotes colorectal cancer cell proliferation and migration by targeting suppressor of cytokine signaling.Oncol Lett. 2018; 16: 65-72
- Interaction of the TNFR-receptor associated factor TRAF1 with I-kappa B kinase-2 and TRAF2 indicates a regulatory function for NF-kappa B signaling.PLoS One. 2010; 5e12683
- Epidemiology and socioeconomic impact of skin disease in lupus erythematosus.Lupus. 1997; 6: 96-104
- Hypersensitive IFN responses in lupus keratinocytes reveal key mechanistic determinants in cutaneous lupus.J Immunol. 2019; 202: 2121-2130
- NF-kB signaling in skin aging.Mech Ageing Dev. 2019; 184111160
- PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer.Int J Biol Markers. 2018; 33: 102-108
- Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies.Nat Rev Rheumatol. 2019; 15: 519-532
- NF-kB in the regulation of epitheial homeostasis and inflammation.Cell Res. 2011; 21: 146-158
- Cooperation between TNF receptor-associated factors 1 and 2 in CD40 signaling.J Immunol. 2006; 176: 5388-5400
- miR-885-5p negatively regulates warburg effect by silencing hexokinase 2 in liver cancer.Mol Ther Nucleic Acids. 2019; 18: 308-319
- MicroRNA-mediated control in the skin.Cell Death Differ. 2010; 17: 229-235
- Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs.Nat Genet. 2006; 38: 356-362
Supplementary References
- Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells.Nat Protoc. 2010; 5: 371-382
- The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus.J Invest Dermatol. 2005; 125: 889-894
- A robust automated measure of average antibody staining in immunohistochemistry images.J Histochem Cytochem. 2010; 58: 95-107
- 1st International Conference on Cutaneous Lupus Erythematosus Düsseldorf, Germany, September 1-5, 2004.Autoimmun Rev. 2005; 4: 66-78
- Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring.Diagn Pathol. 2012; 7: 42
Article info
Publication history
Published online: August 29, 2022
Accepted:
August 1,
2022
Received in revised form:
July 21,
2022
Received:
April 4,
2022
accepted manuscript published online 30 August 2022; corrected proof published online 4 October 2022Identification
Copyright
© 2022 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
