Mechanical Stretch Exacerbates Psoriasis by Stimulating Keratinocyte Proliferation and Cytokine Production

Abstract

Psoriasis is a chronic inflammatory autoimmune skin disease that often occurs in rubbed areas undergoing a strong mechanical stretch, such as the elbows and knees. However, the pathologic role of mechanical tension in psoriasis remains unclear. In this study, we investigated the contribution of keratinocyte mechanical stretch to the clinical features of psoriasis. We found that keratinocyte proliferation and skin barrier-associated gene expression increased significantly after 24 hours of continuous stretching. Additionally, continuous stretching induced the production of psoriasis-associated proinflammatory cytokines, antibacterial peptides, and chemokines in primary human keratinocytes. Furthermore, we established a murine model of skin expansion by implanting a dilator into the dorsum of BALB/c mice to assess the effect of mechanical stretch on the epidermis in vivo. The dilator-implanted mice displayed prominent epidermal hyperproliferation, impaired skin barrier function, and up-regulation of psoriasis-associated cytokines in epidermal keratinocytes. Most importantly, the dilator-implanted psoriatic mice treated with imiquimod or IL-23 displayed an aggravated psoriatic phenotype compared with mice without dilator implantation. Collectively, our results suggest that mechanical stretch can exacerbate psoriatic lesions by promoting cell proliferation and amplifying the production of proinflammatory cytokines by keratinocytes. Thus, our findings provide new insights into the pathogenesis of psoriasis.

Psoriasis and Antimicrobial Peptides

“…Hollox et al showed a significant association between higher genomic copy number for hBD genes and risk of psoriasis [73]. Qiao et al reported that the production of hBD and another AMP, LCN2, increased significantly in keratinocytes following mechanical stretch [74]. In addition, Bhatt et al showed that sustained secretion of S100A7 from differentiated keratinocytes is dependent on the downregulation of caspase-8, and that IL-1α is necessary and sufficient to induce S100A7 secretion [75].…”

Transcriptome Profiling Analyses in Psoriasis: A Dynamic Contribution of Keratinocytes to the Pathogenesis

“…Cutaneous injury activates toll-like receptor 3 in keratinocytes to produce various proinflammatory cytokines, such as TNF-α, IL-6, and IL-36. The production of psoriasis-associated inflammatory cytokines can also be induced by mechanical stretches [ 52 , 53 ]. These studies confirm that cytokines produced by keratinocytes can play a significant role in the development of this condition, and that keratinocytes are important in the initiation of cutaneous inflammation by activating immune cells.…”

Cytokinocytes: the diverse contribution of keratinocytes to immune responses in skin

“…Treatment of keratinocytes with mechanical stimulation activates the secretion of inflammatory cytokines (IL-1α, IL-6, IL-23, and TNF) and chemokines (CXCL1 and CCL20) ( 64 – 66 ). Other studies have reported that mechanical stretching promotes keratinocyte proliferation and inhibits keratinocyte differentiation ( 65 , 67 , 68 ).…”