Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex

Abstract

Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures. The cellular pathology of most EBS subtypes is associated with the fragility of the intermediate filament network, cytolysis of the basal layer of the epidermis, or attenuation of hemidesmosomal/desmosomal components. Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes. Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs. Global changes in cellular signaling mainly occur in cases of severe dominant EBS mutations. The spectrum of changes initiated by phosphorylation includes the inhibition of proteasome degradation, TNF-α signaling activation, deregulated proliferation, abnormal cell migration, and impaired adherence of keratinocytes. ER stress also leads to the release of proinflammatory danger-associated molecular pattern (DAMP) molecules, which enhance avalanche-like inflammation. Many instances of positive feedback in the course of cellular stress and the development of sterile inflammation led to systemic chronic inflammation in EBS. This highlights the role of keratin in the maintenance of epidermal and immune homeostasis.

Mesenchymal stem cells express epidermal markers in an in vitro reconstructed human skin model

“…Specifically, we showed that MSC from umbilical cord contributed to form a stratified organotypic culture but not a typical epithelial structure in both used dermal equivalents—collagen with fibroblasts and the decellularized matrix MatriXpec™, being the structural and chemical characteristics of dermal equivalents critical for the epidermis stratification and keratinocyte complete differentiation. In those organotypic cultures it was verified the expression of essential epidermal molecular markers such as cytokeratins (CK 5 and CK10), involucrin, filaggrin and the epidermal kallikreins (KLK), proteins that are critical to maintaining skin function and homeostasis ( Kalinska et al, 2016 ; Evtushenko et al, 2021 ).…”

Architecture and dynamics of a novel desmosome-endoplasmic reticulum organelle

“…Likewise, intermediate filaments provide cells and tissues with resistance to mechanical and chemical stresses, particularly in the heart, skin, and liver ( 20, 25, 26 ). Interestingly, ER stress has been implicated in epidermal fragility disorders caused by keratin or desmosome dysfunction ( 27 ). Conversely, loss of function mutations in the ER calcium pump SERCA2 cause desmosome and skin defects in Darier’s disease ( 28 ).…”

“…Interestingly, ER stress has been implicated in epidermal fragility disorders caused by keratin or desmosome dysfunction (27). Conversely, loss of function mutations in the ER calcium pump SERCA2 cause desmosome and skin defects in Darier's disease (28) .…”

Effects of Periplaneta americana extracts on the growth and proliferation of cutaneous interstitial cells in cutaneous-wound healing

“…At the same time, it can upregulate glutamine levels; stimulate protein synthesis; and provide nutritional support for mucosal cells, fibroblasts, and other rapidly proliferating cells ( Cheng and Eriksson, 2017 ). Previous studies have shown that KFX can effectively promote angiogenesis and granular-tissue growth, improve wound microcirculation, accelerate tissue repair and regeneration, eliminate edema, and enhance the immune function, which can help repair and heal ulcers as soon as possible, protect the ulcer surface from infection, and avoid necrosis ( Chigurupati et al, 2013 ; Evtushenko et al, 2021 ).…”