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Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes

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Abstract

Dipeptidyl-peptidase 4 (DPP4) is a multifunctional type II transmembrane glycoprotein that is expressed on various cell surfaces. While DPP4 inhibitors have a therapeutic role in the treatment of diabetes mellitus, they are an independent risk factor in the development of bullous pemphigoid. Contrarily, there are reports of improvement in psoriasis with DPP4 inhibition. We investigated the effect of DPP4 inhibition on primary human keratinocytes to determine whether DPP4 modulates keratinocyte inflammatory signaling and keratinocyte homeostasis. We performed RNA sequencing of primary adult human keratinocytes treated with DPP4 inhibitor, identifying 424 differentially expressed genes. Gene ontology analysis revealed significant enrichment of epidermal differentiation and cornified envelope genes. Using three-dimensional organotypic cultures and a pan-late cornified envelope 2 (LCE2) antibody, we demonstrate a dose dependent relationship between DPP4 inhibition and increased expression of LCE2 during epidermal development. The late cornified envelope gene clusters are expressed at the late stages of epithelial development, responding to stimuli such as calcium and ultraviolet light. While its biologic function is not fully understood, mutations in LCE3B/LCE3C confer a 40% increased risk in the development of plaque psoriasis. While we did not identify significant modulation of keratinocyte inflammatory markers, DPP4 inhibition increased expression of the late cornified envelope may offer a potential alternative therapeutic mechanism in psoriasis.

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Code availability

N/A. No new software created. Data analysis code available on request.

Availability of data and material (data transparency)

All databases are available in the supplementary materials.

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Acknowledgements

We thank Dr. Masashi Narita for providing pan-LCE2 antibody.

Funding

Research was supported in part by the Northwestern University Skin Biology and Diseases Resource-based Center of the National Institutes of Health (P30AR075049). Lei Bao received financial support from the Albert H. and Mary Jane Slepyan Endowed Fellowship.

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Authors

Contributions

Lei Bao, Bethany E. Perez White, Payal Patel, and Jing Li performed the experiments. Kyle Amber performed statistical analysis and prepared the manuscript. Lei Bao, Bethany E. Perez White, Payal Patel, and Jing Li contributed towards critical revision of the manuscript. All authors reviewed and approved of the final manuscript.

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Correspondence to Kyle T. Amber.

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The authors declare no potential conflicts of interest.

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This study was exempt from approval by the Ethics Committee at the University of Illinois at Chicago.

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Bao, L., Li, J., Perez White, B.E. et al. Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes. Arch Dermatol Res 314, 909–915 (2022). https://doi.org/10.1007/s00403-021-02249-4

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