Overexpression of Cathepsin S Induces Chronic Atopic Dermatitis in Mice

Abstract

Atopic dermatitis (AD) is a chronically relapsing, non contagious pruritic skin disease with two phases: acute and chronic. Cysteine protease cathepsin S (CTSS) is involved in inflammatory processes, possibly leading to atherosclerosis and asthma. Recently, it has been reported that CTSS can arouse a predominant sensation of itch accompanied by classical ligand–receptor signaling [corrected]. Recently, CTSS was shown to be a ligand for proteinase-activated receptor-2 (PAR-2), which is associated with itching. In this study, we show that CTSS-overexpressing transgenic (TG) mice spontaneously develop a skin disorder similar to chronic AD. The results of this study suggest that CTSS overexpression triggers PAR-2 expression in dendritic cells (DCs), resulting in the promotion of CD4(+) differentiation, which is involved in major histocompatibility complex (MHC) class II expression. In addition, we investigated mast cells and macrophages and found significantly higher mean levels of T helper type 1 (Th1) cell-associated cytokines than T helper type 2 (Th2) cell-associated cytokines in CTSS-overexpressing TG mice. These results suggest that increased PAR-2 expression in DCs as a result of CTSS overexpression induces scratching behavior and Th1 cell-associated cytokine expression, and can trigger chronic AD symptoms.

Mrgprs activation is required for chronic itch conditions in mice

“…The expression of cathepsin S is upregulated in psoriatic keratinocytes [33]. Mice carrying a transgene expressing cathepsin S spontaneously develop atopic dermatitis [34]. Der p1 is a prominent allergen from house dust mite and has been involved in the allergic inflammatory processes in both skin [35, 36] and the respiratory system [37].…”

Why we scratch an itch: the molecules, cells and circuits of itch

“…Unlike SLIGRL, tryptase does not activate rodent MrgprC11 or human MrgprX1, suggesting that SLIGRL is not equivalent to the natural tethered ligand in vivo 12 . In fact, PAR2 activation by SLIGRL, tryptase or cathepsin S also promotes the release of the cytokine, thymic stromal lymphopoietin (TSLP) from keratinocytes, indicating that intricate multicellular pathways may underlie chronic itch 12,27 . TSLP is a robust pruritogen associated with atopic dermatitis that activates a subset of neurons expressing TRPA1- and TSLP receptor (TSLPR) ( Fig.…”

Itch Mechanisms and Circuits

“…It was recently identified as a new pruritogen because the application of cathepsin S on human skin induced the itch sensation (108). Cathepsin S–overexpressing transgenic mice spontaneously develop atopic dermatitis and severe itching (64). Both mucunain and cathepsin S activate PAR2 and PAR4 in heterologous systems (107, 108).…”