Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration

Zhao, Jingling; Yu, Jianxing; Xu, Yingbin; Chen, Lei; Zhou, Fei; Zhai, Qiyi; Wu, Jun; Shu, Bin; Qi, Shunan

doi:10.1016/j.jid.2018.04.036

Cited by 25 publications

(25 citation statements)

References 43 publications

(49 reference statements)

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“…Robustly, five of them examining col-I production reported enhanced col-I production when keratinocytes were dehydrated compared to their normally hydrated counterpart. When tested, consistently with the results on col-I, αSMA expression was increased by dehydration in three of three papers (15,19,22). One of these papers focused on MMPs and TIMP-1 showing that hydration enhances MMP1, MMP8, and MMP13 and decreases TIMP-1 production (34).…”

Section: Effect Of Soluble Factors and Physical Stress Acting On Kerasupporting

confidence: 68%

“…Within the context of wound healing, the effects on fibroblasts of dehydration or hyper-hydration of partially stratified keratinocytes was investigated in six papers (15,19,22,34,52). Robustly, five of them examining col-I production reported enhanced col-I production when keratinocytes were dehydrated compared to their normally hydrated counterpart.…”

Section: Effect Of Soluble Factors and Physical Stress Acting On Keramentioning

confidence: 99%

“…Chemokine (C-C motif) ligand (CCL)26 (eotaxin-3) production by keratinocytes was reported to enhance fibroblast proliferation and motility (27). High mobility group box 1 (HMGB1) production by keratinocytes was reported to enhance fibroblast activation and αSMA expression (15). One study reported that parathyroid hormone-related protein (PTHrP) released by keratinocytes enhanced the production of KGF by fibroblasts (85).…”

Section: Soluble Mediators Of Inflammation Influencing the Crosstalk mentioning

confidence: 99%

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Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders

2020

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Background/Objective: Skin fibrosis is the result of aberrant processes leading to abnormal deposition of extracellular matrix (ECM) in the dermis. In healthy skin, keratinocytes participate to maintain skin homeostasis by actively crosstalking with fibroblasts. Within the wide spectrum of fibrotic skin disorders, relatively little attention has been devoted to the role of keratinocytes for their capacity to participate to skin fibrosis. This systematic review aims at summarizing the available knowledge on the reciprocal interplay of keratinocytes with fibroblasts and their soluble mediators in physiological states, mostly wound healing, and conditions associated with skin fibrosis. Methods: We performed a systematic literature search on PubMed to identify in vitro and ex vivo human studies investigating the keratinocyte characteristics and their interplay with fibroblasts in physiological conditions and within fibrotic skin disorders including hypertrophic scars, keloids, and systemic sclerosis. Studies were selected according to pre-specified eligibility criteria. Data on study methods, models, stimuli and outcomes were retrieved and summarized according to pre-specified criteria. Results: Among the 6,271 abstracts retrieved, 73 articles were included, of which 14 were specifically dealing with fibrotic skin pathologies. Fifty-six studies investigated how keratinocyte may affect fibroblast responses in terms of ECM-related genes or protein production, phenotype modification, and cytokine production. Most studies in both physiological conditions and fibrosis demonstrated that keratinocytes stimulate fibroblasts through the production of interleukin 1, inducing keratinocyte growth factor (KGF) and metalloproteinases in the fibroblasts. When the potential of keratinocytes to modulate collagen synthesis by healthy fibroblasts was explored, the results were controversial. Nevertheless, studies investigating keratinocytes from fibrotic skin, including keloids, hypertrophic scar, and scleroderma, suggested their potential involvement in enhancing ECM deposition. Twenty-three papers investigated keratinocyte proliferation differentiation and production of soluble mediators in response to interactions with fibroblasts. Most studies showed that fibroblasts modulate keratinocyte viability, proliferation, and differentiation. The production of KGF by fibroblast was identified as key for these functions. Conclusions: This review condenses evidence for the active interaction between keratinocytes and fibroblasts in maintaining skin homeostasis and the altered homeostatic interplay between keratinocytes and dermal fibroblasts in scleroderma and scleroderma-like disorders.

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Section: Effect Of Soluble Factors and Physical Stress Acting On Kerasupporting

confidence: 68%

Section: Effect Of Soluble Factors and Physical Stress Acting On Keramentioning

confidence: 99%

Section: Soluble Mediators Of Inflammation Influencing the Crosstalk mentioning

confidence: 99%

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Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders

2020

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“…This could be due to an accelerated differentiation program and barrier formation as response to the lower external water level, inducing temporary but fierce signalling for barrier repair responses [20]. In addition, reduced RH levels affected the activation of dermal fibroblasts, which could contribute to more epidermal activation [56, 57]. As an activated epidermis is shown to undermine the lipid barrier formation in vitro and in vivo [9, 41], lower in vitro RH levels are not recommended.…”

Section: Discussionmentioning

confidence: 99%

Unravelling effects of relative humidity on lipid barrier formation in human skin equivalents

et al. 2019

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Relative humidity (RH) levels vary continuously in vivo, although during in vitro generation of three-dimensional human skin equivalents (HSEs) these remain high (90–95%) to prevent evaporation of the cell-culture medium. However, skin functionality is directly influenced by environmental RH. As the barrier formation in HSEs is different, there is a need to better understand the role of cell-culture conditions during the generation of HSEs. In this study, we aim to investigate the effects of RH on epidermal morphogenesis and lipid barrier formation in HSEs. Therefore, two types of HSEs were developed at 90% or at 60% RH. Assessments were performed to determine epidermal morphogenesis by immunohistochemical analyses, ceramide composition by lipidomic analysis, and lipid organization by Fourier transform infrared spectroscopy and small-angle X-ray diffraction. We show that reduction of RH mainly affected the uppermost viable epidermal layers in the HSEs, including an enlargement of the granular cells and induction of epidermal cell activation. Neither the composition nor the organization of the lipids in the intercorneocyte space were substantially altered at reduced RH. In addition, lipid processing from glucosylceramides to ceramides was not affected by reduced RH in HSEs as shown by enzyme expression, enzyme activity, and substrate-to-product ratio. Our results demonstrate that RH directly influences epidermal morphogenesis, albeit the in vitro lipid barrier formation is comparable at 90% and 60% RH.Electronic supplementary materialThe online version of this article (10.1007/s00403-019-01948-3) contains supplementary material, which is available to authorized users.

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“…Upon skin injury, it could drive infiltration of inflammatory cells and increase collagen synthesis by fibroblasts. HMGB1 secreted from keratinocytes activated fibroblasts by promoting the nuclear import of MRTF-A, increased the nuclear accumulation of MRTF-A/SRF complexes and consequently enhanced a-smooth muscle actin promoter activation (70). Application of HMGB1 inhibitor BoxA significantly suppressed scar formation in rabbit (70).…”

Section: Inhibitors Of Dampsmentioning

confidence: 99%

The Roles of Inflammation in Keloid and Hypertrophic Scars

et al. 2020

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The underlying mechanisms of wound healing are complex but inflammation is one of the determining factors. Besides its traditional role in combating against infection upon injury, the characteristics and magnitude of inflammation have dramatic impacts on the pathogenesis of scar. Keloids and hypertrophic scars are pathological scars that result from aberrant wound healing. They are characterized by continuous local inflammation and excessive collagen deposition. In this review, we aim at discussing how dysregulated inflammation contributes to the pathogenesis of scar formation. Immune cells, soluble inflammatory mediators, and the related intracellular signal transduction pathways are our three subtopics encompassing the events occurring in inflammation associated with scar formation. In the end, we enumerate the current and potential medicines and therapeutics for suppressing inflammation and limiting progression to scar. Understanding the initiation, progression, and resolution of inflammation will provide insights into the mechanisms of scar formation and is useful for developing effective treatments.

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Epidermal HMGB1 Activates Dermal Fibroblasts and Causes Hypertrophic Scar Formation in Reduced Hydration

Cited by 25 publications

References 43 publications

Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders

Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders

Unravelling effects of relative humidity on lipid barrier formation in human skin equivalents

The Roles of Inflammation in Keloid and Hypertrophic Scars

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