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

Abstract

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.

Accelerated Wound Healing in Diabetic Rat by miRNA-185-5p and Its Anti-Inflammatory Activity

“… 3 Studies have shown that the pathogenic phenotype leading to chronic inflammation in diabetic wounds is associated with the effects of the reactive glucose metabolite methylglyoxal, 15 AGEs, 16 and migration inhibitor (MIF) on dermal cells. 6 Dermal fibroblasts from diabetic donors exhibited insulin-induced decreased glucose uptake and reduced insulin receptor expression.…”

“… 3 Long-term hyperglycemia promotes the activation of NF-κB, 4 leading to chronic inflammation 5 and impairing skin fibroblast activation. 6 Difficult healing of foot ulcers in diabetes is a complex problem in clinical diseases. However, the treatment of refractory diabetic foot ulcers is insufficient, and better therapeutic interventions are urgently needed.…”

“…In vitro culture of dermal fibroblasts from diabetic donors exhibited Increased secretion of IL-6 and MIF in fibroblasts from diabetic donors and decreased secretion of procollagen type I C peptide (PICP, a marker of collagen production). 6 How to improve the low inflammatory state of diabetic skin fibroblasts to facilitate the closure of diabetic foot refractory ulcers deserves our consideration.…”

Clostridium botulinum C3bot mediated effects on cytokine-induced psoriasis-like phenotype in full-thickness skin model

“…The epidermis becomes thick with overgrowth of the stratum corneum containing immature keratinocytes and alternated expression of tight junction proteins like claudin-1 and zonula occludens-1 (Yoshida et al 2001 ; Pummi et al 2001 ). A large number of cytokines and chemokines have been proposed to contribute to the pathogenesis of psoriasis (Nickoloff et al 2007 ). In this context, an increased transcript level of pro-inflammatory factors such as IL-6 is the essential hallmark of the disease (Grossman et al 1989 ; Fujishima et al 2010 ; Johnston et al 2013 ) in addition to further described cytokines important in psoriasis pathogenesis such as TNF-alpha, IL-22 and IL-17 (Zheng et al 2007 ; Nickoloff 2007 ).…”

Secretion of IL-6 by fibroblasts exposed to Australian honeys involves lipopolysaccharide and is independent of floral source

“…In addition to their role in extracellular matrix production and scar tissue formation, fibroblasts release cytokines to provide regulatory control over immune cell function 1 . Dermal fibroblasts basally secrete tumour necrosis factor alpha (TNF-α), interferon gamma, interleukin-6 (IL-6) and IL-12, with elevated secretions in response to stimuli such as histamine and bacterial lipopolysaccharide (LPS) 2 , 3 . The release of cytokines by wound fibroblasts during inflammation leads to the activation of nearby immune cells 1 .…”