Mechanotransduction in Skin Inflammation

Abstract

In the process of mechanotransduction, the cells in the body perceive and interpret mechanical stimuli to maintain tissue homeostasis and respond to the environmental changes. Increasing evidence points towards dysregulated mechanotransduction as a pathologically relevant factor in human diseases, including inflammatory conditions. Skin is the organ that constantly undergoes considerable mechanical stresses, and the ability of mechanical factors to provoke inflammatory processes in the skin has long been known, with the Koebner phenomenon being an example. However, the molecular mechanisms and key factors linking mechanotransduction and cutaneous inflammation remain understudied. In this review, we outline the key players in the tissue's mechanical homeostasis, the available data, and the gaps in our current understanding of their aberrant regulation in chronic cutaneous inflammation. We mainly focus on psoriasis as one of the most studied skin inflammatory diseases; we also discuss mechanotransduction in the context of skin fibrosis as a result of chronic inflammation. Even though the role of mechanotransduction in inflammation of the simple epithelia of internal organs is being actively studied, we conclude that the mechanoregulation in the stratified epidermis of the skin requires more attention in future translational research.

Keywords: actin-myosin cytoskeleton; atopic dermatitis; cytokines; epidermis; fibrosis; integrins; intermediate filaments; keratinocyte; psoriasis; stretch.

Figure 1

A scheme of the epidermis and dermis in normal skin (A), psoriasis (B) and fibrosis (C). Morphologically, psoriatic inflammation is characterized by epidermal hyperproliferation and thickening (acanthosis), an increased infiltration of immune cells into the dermis and epidermis, alterations in the composition of the dermal ECM, and damage to the BM. Fibrotic skin is characterized by excessive ECM deposition by the dermal myofibroblasts and an increased presence of immune cells in the dermis. Figure created in Biorender.com 14.06.2022.

Figure 2

Integration of different mechanotransduction mechanisms during inflammation in skin cells. The cell senses forces and ECM structures via engagement of channels and adhesion receptors, which physically and biochemically connect to the cytoskeletal systems inside the cell. The alterations of the intercellular signaling pathways, together with the mechanical load on the nucleus, adjusts the gene expression. Figure created in Biorender.com 14.06.2022.

Figure 3

Dysregulation of mechanotransduction-related proteins in psoriatic skin revealed by immunofluorescence. (A) Collagen IV is generally lost from the BM and tenascin-C is overexpressed in the dermis of psoriatic skin. (B) Integrin αv is upregulated in the dermis. (C) In normal skin, MLCK has higher expression in the basal layer of the epidermis, whereas in psoriatic skin, it is increased in all epidermal layers. (D) β-Catenin is downregulated at the epidermal cell junctions. (E) The phosphorylated myosin light chain (Thr18/Ser19) underlies the cell borders in the upper epidermal layers in normal skin and the continuous pattern is lost in psoriatic epidermis. (F) YAP localizes to the nucleus in the basal layer, but not in the upper layers in the normal epidermis, whereas its nuclear localization is retained in multiple layers of a psoriatic epidermis. DAPI is in blue. Scale bar, 100 μm.