Abstract
Matrix stiffness, a critical physical property of the cellular environment, is implicated in epidermal homeostasis. In particular, matrix stiffening during the pathological progression of skin diseases appears to contribute to cellular responses of keratinocytes. However, it has not yet elucidated the molecular mechanism underlying matrix-stiffness-mediated signaling in coordination with chemical stimuli during inflammation and its effect on proinflammatory cytokine production. In this study, we demonstrated that keratinocytes adapt to matrix stiffening by increasing cell–matrix adhesion via actin cytoskeleton remodeling. Specifically, mechanosensing and signal transduction are coupled with chemical stimuli to regulate cytokine production, and interleukin-6 (IL-6) production is elevated in keratinocytes on stiffer substrates in response to 2,4-dinitrochlorobenzene. We demonstrated that β1 integrin and focal adhesion kinase (FAK) expression were enhanced with increasing stiffness and activation of ERK and the PI3K/Akt pathway was involved in stiffening-mediated IL-6 production. Collectively, our results reveal the critical role of matrix stiffening in modulating the proinflammatory response of keratinocytes, with important clinical implications for skin diseases accompanied by pathological matrix stiffening.
Highlights
The skin is the interface between the environment and inner tissues and is constantly exposed to diverse external stimuli such as mechanical stresses or toxic chemicals
Cell growth tracking revealed a more rapid increase in the number of cells on the stiff substrate from day 2, and the difference gradually increased over the 4 days, which is consistent with the results of previous studies [10, 12] (Supplementary Figure S2)
Further elucidation of the mechanism by which matrix stiffening regulates the inflammatory response of keratinocytes in the context of cytokine production is essential for understanding the role of mechanical cues in the pathogenesis of skin diseases with matrix stiffening and future therapeutic interventions for these diseases
Summary
The skin is the interface between the environment and inner tissues and is constantly exposed to diverse external stimuli such as mechanical stresses or toxic chemicals. Keratinocytes, a main component of the epidermis, are known to form physical and immunological barriers against these stimuli through the production of proinflammatory cytokines such as interleukin-6 (IL-6), IL-1a, Matrix Stiffening-Induced IL-6 Secretion in Keratinocytes tumor necrosis factor (TNF)-a, interferon (IFN) g, and CXC motif ligand 8 (CXCL8) [1,2,3] These keratinocyte responses are considered to trigger subsequent inflammatory events by recruiting and activating other immune cells in the skin to maintain skin homeostasis [4,5,6]. Matrix-stiffness-mediated mechanical cues are considered essential for disease pathogenesis via the elaboration of keratinocyte-derived cytokines; targeting the mechanotransduction pathway is clinically highly effective for the treatment of skin diseases with pathological matrix stiffening. It is not completely understood how matrixstiffness-mediated mechanical cues regulate inflammatory cytokine production in keratinocytes in coordination with chemical cues during inflammation
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