Contribution of keratinocytes to dermal fibrosis

Abstract

Purpose of reviewThe cellular pathogenesis of fibrotic disorders including systemic sclerosis (SSc) remains largely speculative. Currently, the altered function of endothelial cells and fibroblasts under the influence of an inappropriate immune response are considered central pathogenic events in SSc. Adding to this complexity, novel evidence here reviewed suggests that keratinocytes may concur in the development of skin fibrosis.Recent findingsEpidermal equivalents (EE) generated from primary SSc keratinocytes display a distinct gene expression program when compared to healthy donor (HD) EE. SSc-EE, among others, exhibited enhanced oxidative and metabolic response pathways. Immunohistochemical studies demonstrated similarities between SSc-EE and SSc epidermis including altered keratinocyte differentiation, enhanced expression of activation markers, and reduced rate of basal keratinocytes proliferation. SSc-EE supernatants more than HD-EE modified the inflammatory and extracellular matrix deposition/resorption program of dermal fibroblasts. Further evidence indicated that the relative lack rather than the excess of interleukin-25 in keratinocytes may contribute to enhanced dermal fibrotic changes. Overall, these data support keratinocyte-intrinsic SSc-related modifications.SummaryImproved methods for engineering epidermal and skin equivalents are helping to address the question whether keratinocyte alterations in SSc are primary and capable to dysregulate dermal homeostasis or secondary following dermal fibrotic changes.

Immune cells in the epithelial immune microenvironment of psoriasis: emerging therapeutic targets

“…In autoimmune-mediated skin diseases such as psoriasis, KCs, DCs, macrophages, neutrophils, and T cells assume a pivotal role ( 80 , 89 ). KCs are primarily situated in the outermost layer of the epidermis, forming the stratum corneum, a fundamental component of the epidermis ( 90 ) ( 91 ). They represent the innate immune constituents within the skin’s immune system, actively combating external pathogens and engaging in immune and inflammatory responses ( 18 , 92 ).…”