Elevated skin surface pH has been reported in patients with atopic dermatitis (AD). Here we explored the role of skin pH in the pathogenesis of AD using the NC/Tnd murine AD model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free (SPF) conditions induced KLK5 and activated the protease-activated receptor 2 (PAR2), resulting in thymic stromal lymphopoietin (TSLP) secretion and a cutaneous T-helper 2 allergic response. This was associated with increased trans-epidermal water loss and development of eczematous lesions in these SPF NC/Tnd mice, which normally do not suffer from AD. Injection of recombinant TSLP also induced scratching behavior in the SPF NC/Tnd mice. TSLP production and dermatitis induced by alkalinization of the skin could be blocked by the PAR2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein (KLK) 5　activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger NHE1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate KLK5 activity leading to skin barrier dysfunction, itch, and dermatitis via the PAR2-TSLP pathway.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.363.

IL-31, which is a member of the IL-6 family of cytokines, is produced mainly by activated CD4+ T cells, in particular activated Th2 cells, suggesting a contribution to development of type-2 immune responses. IL-31 was reported to be increased in specimens from patients with atopic dermatitis, and IL-31-transgenic mice develop atopic dermatitis-like skin inflammation, which is involved in the pathogenesis of atopic dermatitis. However, the role of IL-31 in development of contact dermatitis/contact hypersensitivity (CHS), which is mediated by hapten-specific T cells, including Th2 cells, is not fully understood. Therefore, we investigated this using IL-31-deficient (Il31−/−) mice, which we newly generated. We demonstrated that the mice showed normal migration and maturation of skin dendritic cells and induction of hapten-specific T cells in the sensitization phase of FITC-induced CHS, and normal induction of local inflammation in the elicitation phase of FITC- and DNFB-induced CHS. On the other hand, those mice showed reduced scratching frequency and duration during FITC- and/or DNFB-induced CHS. Our findings suggest that IL-31 is responsible for pruritus, but not induction of local skin inflammation, during CHS induced by FITC and DNFB.

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.

We analyze a model of spinless fermions on a triangular lattice at half-filling interacting via strong nearest-neighbor repulsive interactions, V , using the variational Monte Carlo simulation technique. The existence of three-sublattice long-range order is confirmed by the finite-size scaling analysis of the charge structural factor at Vc/t 12. This ordered phase shows characteristics expected for a so called "pinball liquid" state, which has the spontaneous separation of fermionic degrees of freedom into coexisting Wigner crystal-like charge order (pin) and a metal (ball). The pins are fixed in order to maximize the kinetic energy gain of balls which move almost freely. The Fermi surface is reconstructed at V = Vc and remains towards the strong coupling limit. These features reminiscent of the strong correlation together with the large value of Vc/t distinguishes the pinball liquid from the conventional charge-density-wave.