Kallikrein 7 Promotes Atopic Dermatitis-Associated Itch Independently of Skin Inflammation

Abstract

Atopic dermatitis (AD) is a highly prevalent, itchy inflammatory skin disorder that is thought to arise from a combination of skin barrier defect and immune dysregulation. Kallikreins (KLK), a family of serine proteases with a diverse array of homeostatic functions, including skin desquamation and innate immunity, are hypothesized to contribute to AD pathogenesis. However, their precise role in AD has not been clearly defined. In this study, RNA sequencing analyses identified KLK7 as the most abundant and differentially expressed KLK in both human AD and murine AD-like skin. Further, in mice, Klk7 expression was localized to the epidermis in both steady state and inflammation. Unexpectedly, KLK7 was dispensable for the development of ADassociated skin inflammation. Instead, KLK7 was selectively required for AD-associated chronic itch. Even without the alleviation of skin inflammation, KLK7-deficient mice exhibited significantly attenuated scratching, compared with littermate controls, after AD-like disease induction. Collectively, our findings indicate that KLK7 promotes AD-associated itch independently from skin inflammation and reveal a previously unrecognized epidermal-neural mechanism of AD associated itch.

SnapshotDx Quiz: September 2020

“…In fact, it has been proposed that KLK5 autoactivates and initiates a cascade to subsequently activate KLK7 (Brattsand et al, 2005). Guo et al (2020) note that in previous studies, multiple KLKs, including KLK5 and KLK7, are increased in AD (Komatsu et al, 2007;Morizane et al, 2012;Vasilopoulos et al, 2011). However, in this study, the authors report that there were no increases in KLK5 expression in lesional AD skin and that only KLK7 was selectively overexpressed.…”

“…In addition, c-Fos expression, which is induced by the activation of spinal dorsal horn neurons, was found to be decreased in thoracic spinal cords of Klk7 À/À mice (Gao and Ji, 2009). In summary, Guo et al (2020) provide evidence that KLK7 is critical for the activation of itch-associated neural pathways and measurable itch behavior.…”

“…a. AD-association skin inflammation: According to Guo et al (2020), KLK7 was not essential for the development of AD-associated skin inflammation. In this study, topical application of MC903 (vitamin D3 analog, calcipotriene) induced an AD-like condition in mice.…”

The Proteolytic Network in Palmoplantar Keratoderma: SERPINA12 Joins the Family

“…SERPINA12 acts to inhibit the serine proteases kallikrein (KLK) 7 and KLK14 (Weiner et al, 2019). These KLKs are predominantly expressed in the epidermis (Guo et al, 2020). Their most wellcharacterized function is the degradation of intercellular junction components, such as desmoglein-1, desmocollin-1, and corneodesmosin (Kishibe, 2019).…”

“…When an AD-like disease is induced in mice, KLK7 knockout (Klk7 À/À ) does not significantly change skin inflammation nor key inflammatory markers (Guo et al, 2020). Although spontaneous scratching is markedly reduced, pruritus does not appear to be a major feature of the SER-PINA12 mutant PPK.…”