Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors

The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different type...

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Autores principales:	Kimberly Nickel, Ursula Wensorra, Horst Wenck, Nils Peters, Harald Genth
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	diabetes skin glyoxalase I MIF Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5d6471c65a1549b489b49d61d3cf793b
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spelling	oai:doaj.org-article:5d6471c65a1549b489b49d61d3cf793b2021-11-25T17:09:09ZEvaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors10.3390/cells101129312073-4409https://doaj.org/article/5d6471c65a1549b489b49d61d3cf793b2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2931https://doaj.org/toc/2073-4409The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different types of cells by either direct contact or by autocrine and paracrine signalling. Diabetic skin is characterized by itching, numbness, ulcers, eczema, and other pathophysiological changes. These pathogenic phenotypes have been associated with the effects of the reactive glucose metabolite methylglyoxal (MGO) on dermal cells. In this study, dermal fibroblasts were isolated from diabetic and non-diabetic human donors. Cultured dermal fibroblasts from diabetic donors exhibited reduced insulin-induced glucose uptake and reduced expression of the insulin receptor. This diabetic phenotype persists under cell culture conditions. Secretion of IL-6 was increased in fibroblasts from diabetic donors. Increased secretion of IL-6 and MIF was also observed upon the treatment of dermal fibroblasts with MGO, suggesting that MGO is sufficient for triggering these immunomodulatory responses. Remarkably, MIF treatment resulted in decreased activity of MGO-detoxifying glyoxalase-1. Given that reduced glyoxalase activity results in increased MGO levels, these findings suggested a positive-feedback loop for MGO generation, in which MIF, evoked by MGO, in turn blocks MGO-degrading glyoxalase activity. Finally, secretion of procollagen Type I C-Peptide (PICP), a marker of collagen production, was reduced in fibroblast from diabetic donors. Remarkably, treatment of fibroblasts with either MGO or MIF was sufficient for inducing reduced PICP levels. The observations of this study unravel a signalling network in human dermal fibroblasts with the metabolite MGO being sufficient for inflammation and delayed wound healing, hallmarks of T2D.Kimberly NickelUrsula WensorraHorst WenckNils PetersHarald GenthMDPI AGarticlediabetesskinglyoxalase IskinMIFBiology (General)QH301-705.5ENCells, Vol 10, Iss 2931, p 2931 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	diabetes skin glyoxalase I skin MIF Biology (General) QH301-705.5
spellingShingle	diabetes skin glyoxalase I skin MIF Biology (General) QH301-705.5 Kimberly Nickel Ursula Wensorra Horst Wenck Nils Peters Harald Genth Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
description	The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different types of cells by either direct contact or by autocrine and paracrine signalling. Diabetic skin is characterized by itching, numbness, ulcers, eczema, and other pathophysiological changes. These pathogenic phenotypes have been associated with the effects of the reactive glucose metabolite methylglyoxal (MGO) on dermal cells. In this study, dermal fibroblasts were isolated from diabetic and non-diabetic human donors. Cultured dermal fibroblasts from diabetic donors exhibited reduced insulin-induced glucose uptake and reduced expression of the insulin receptor. This diabetic phenotype persists under cell culture conditions. Secretion of IL-6 was increased in fibroblasts from diabetic donors. Increased secretion of IL-6 and MIF was also observed upon the treatment of dermal fibroblasts with MGO, suggesting that MGO is sufficient for triggering these immunomodulatory responses. Remarkably, MIF treatment resulted in decreased activity of MGO-detoxifying glyoxalase-1. Given that reduced glyoxalase activity results in increased MGO levels, these findings suggested a positive-feedback loop for MGO generation, in which MIF, evoked by MGO, in turn blocks MGO-degrading glyoxalase activity. Finally, secretion of procollagen Type I C-Peptide (PICP), a marker of collagen production, was reduced in fibroblast from diabetic donors. Remarkably, treatment of fibroblasts with either MGO or MIF was sufficient for inducing reduced PICP levels. The observations of this study unravel a signalling network in human dermal fibroblasts with the metabolite MGO being sufficient for inflammation and delayed wound healing, hallmarks of T2D.
format	article
author	Kimberly Nickel Ursula Wensorra Horst Wenck Nils Peters Harald Genth
author_facet	Kimberly Nickel Ursula Wensorra Horst Wenck Nils Peters Harald Genth
author_sort	Kimberly Nickel
title	Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
title_short	Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
title_full	Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
title_fullStr	Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
title_full_unstemmed	Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors
title_sort	evaluation of immunomodulatory responses and changed wound healing in type 2 diabetes—a study exploiting dermal fibroblasts from diabetic and non-diabetic human donors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5d6471c65a1549b489b49d61d3cf793b
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Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors

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