Zhikun Zhang

We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyte-selective ablation of retinoid X receptors (RXRs) -alpha and -beta in the mouse (RXRalphabeta(ep-/-) mice), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [1alpha,25-(OH)(2)D(3); calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in RXRalphabeta(ep-/-) mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RARgamma-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with 1alpha,25-(OH)(2)D(3). Our data demonstrate that RXR/vitamin D receptor and RXR/retinoic acid receptor-gamma heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.

Atopic dermatitis (AD) is often the initial step in the "atopic march," given that more than half of AD patients with moderate to severe AD develop asthma later in life. Both AD and asthma share a similar "atopy" phenotype that includes T helper type 2 inflammation with eosinophilia and hyper-IgE immunoglobulinemia, but the molecular mechanisms underlying the "atopic march" remain elusive. In the present study, we show that induced expression of thymic stromal lymphopoietin (TSLP) in mouse epidermal keratinocytes upon topical application of MC903 (a low calcemic analogue of vitamin D3) not only triggers AD as we previously reported but also aggravates experimental allergic asthma induced by ovalbumin sensitization and challenge. Our study, which provides a mouse model to study human "atopic march," indicates that keratinocyte-produced TSLP may represent an important factor in the link of atopic dermatitis to asthma.

BACKGROUND: Bacterial infection in wounds has become a major threat to human life and health. With the growth use of synthetic antibiotics and the elevated evolution of drug resistant bacteria in human body cells requires the development of novel wound curing strategies. Herein, a novel pH-responsive hydrogel (RPC/PB) was fabricated using poly(vinyl alcohol)-borax (PB) and natural antibiotic resveratrol grafted cellulose nanofibrils (RPC) for bacterial-infected wound management. RESULTS: In this hydrogel matrix, RPC conjugate was interpenetrated in the PB network to form a semi-interpenetrating network that exhibited robust mechanical properties (fracture strength of 149.6 kPa), high self-healing efficiency (> 90%), and excellent adhesion performance (tissue shear stress of 54.2 kPa). Interestingly, the induced RPC/PB hydrogel showed pH-responsive drug release behavior, the cumulative release amount of resveratrol in pH 5.4 was 2.33 times than that of pH 7.4, which was adapted well to the acidic wound microenvironment. Additionally, this RPC/PB hydrogel exhibited excellent biocompatibility and antioxidant effect. Moreover, in vitro and in vivo results revealed that such RPC/PB hydrogel had excellent antibacterial, skin tissue regeneration and wound closure capabilities. CONCLUSION: Therefore, the generated RPC/PB hydrogel could be an excellent wound dressing for bacteria-infected wound healing.