The Role of Chronic Inflammation in Cutaneous Fibrosis: Fibroblast Growth Factor Receptor Deficiency in Keratinocytes as an Example

Abstract

Fibrosis is associated with a variety of skin diseases and causes severe aesthetic and functional impairments. Functional studies in rodents, together with clinical observations, strongly suggest a crucial role of chronic injury and inflammation in the pathogenesis of fibrotic diseases. The phenotype of mice lacking fibroblast growth factor (FGF) receptors 1 and 2 in keratinocytes supports this concept. In these mice, a defect in keratinocytes alone initiated an inflammatory response, which in turn caused keratinocyte hyperproliferation and dermal fibrosis. As the mechanism underlying this phenotype, we identified a loss of FGF-induced expression of claudins and occludin, which caused abnormalities in tight junctions with concomitant deficits in epidermal barrier function. This resulted in severe transepidermal water loss and skin dryness. In turn, activation of keratinocytes and epidermal γδ T cells occurred, which produced IL-1 family member 8 and S100A8 and S100A9. These cytokines attracted immune cells and activated fibroblasts, resulting in a double paracrine loop through production of keratinocyte mitogens by dermal cells. In addition, a profibrotic response was induced in fibroblasts. Our results highlight the importance of an intact epidermal barrier for the prevention of inflammation and fibrosis and the role of chronic inflammation in the pathogenesis of fibrotic diseases.

An observational cross-sectional survey of rosacea: clinical associations and progression between subtypes

“…Animal studies have demonstrated that chronic inflammation is a critical feature in the pathogenesis of cutaneous fibrosis. 19 Previous surveys have also observed the association of male sex with phymatous rosacea. 20,21 We did not observe a significant association of OC with either ETR or PPR.…”

“…19 The clinical distinction between facial erythema of rosacea from that due to photodamage is difficult. In this study, central facial distribution of erythema and photographic representations from the NRSEC were used as a guide to case-finding.…”

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

“…Keratinocytes are critical regulators of fibroblast activity during wound healing, and recent studies suggest that the epidermis can play an active role in dermal fibrosis [67–70]. Defects in epidermal integrity can promote fibrosis indirectly by increasing inflammation, which leads to profibrotic stimulation of fibroblasts, or directly by secretion of paracrine factors that regulate fibroblast proliferation and matrix production.…”

FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin

“…Furthermore, we also did not observe a granulomatous reaction that could impair contraction. Rather, it seems probable that the alterations in the connective tissue that develop in these mice (Meyer et al, 2011) are responsible for the impaired wound contraction.…”