Elevated Kallikrein 7 Expression Tied to Itch in Atopic Dermatitis

A man scratching his itchy skin
A man scratching his itchy skin
An emerging paradigm in itch biology is supported by findings that suggest KLK7 as an influence in the disease pathogenesis of atopic dermatitis.

Elevated kallikrein 7 (KLK7) expression was associated with chronic itch in patients with atopic dermatitis (AD), according to study data published in the Journal of Investigative Dermatology. In mouse models, KLK7 expression appeared to drive AD-associated itch independent of skin inflammation status.

Investigators at the Washington University School of Medicine reanalyzed RNA-sequencing (RNA-seq) data from a published study of patients with and without AD. An unbiased analysis of the data was conducted to identify the most abundant differentially expressed genes in AD. Human biopsy samples were obtained from the university’s clinic patients and separately analyzed for KLK expression using real-time quantitative polymerase chain reaction (RT-qPCR). Investigators analyzed RNA-seq data from a published study of mice with irritant-induced AD-like disease for KLK expression status. Investigators also developed an AD-like disease model of mice with and without elevated KLK7 expression. KLK7-deficient and KLK7-enhanced mice were compared for disease severity and skin inflammation.  

Consistent with prior studies, KLK analysis demonstrated that KLK5 and KLK7 were the most highly expressed KLKs in the skin of control patients. In patients with AD, increased expression of KLK7, KLK8, KLK10, and KLK11 was observed. The increase in expression of KLK7 was more pronounced than that of the other KLKs; KLK7 expression was significantly elevated in AD lesion sites compared with nonlesion sites. Although prior research suggests that KLK5 may be upregulated in the skin of patients with AD, the present analyses found no increased KLK5 expression in AD lesion biopsy specimens. In mouse models, KLK7 expression increased 4-fold in AD-like skin compared with control skin. Increased KLK5 expression was not observed.

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In the in vivo models, KLK7 appeared to be solely expressed in the epidermis during the control state; KLK7 was not detected in the dermal skin, neural tissues, or immune tissues of the skin of control mice. However, after induction of AD-like disease, KLK7 expression was enhanced in the epidermis and became detectable in immune cells and peripheral fibers of sensory neurons. KLK7-deficient mice displayed markedly reduced scratching behaviors compared with KLK7-abundant mice, independent of skin inflammation status. However, KLK7-deficient mice displayed no improvements in AD disease severity compared with mice with enhanced KLK7 expression.

Based on these results, investigators hypothesized that the “epithelial cell-derived KLK7 is [critical] for the development of AD.” As such, therapeutic agents targeting KLK7 may have utility for AD symptom reduction. Given the epidermal expression of KLK7, investigators wrote, therapy could be delivered topically to reduce the risk for side effects.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Guo CJ, Mack MR, Oetjen LK, et al. Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation [published online December 26, 2019]. J Invest Dermatol. doi: 10.1016/j.jid.2019.10.022