The Journal of investigative dermatology最新文献

Fetal skin at early gestational stage is able to regenerate and heal rapidly after wounding. The exact mechanisms and molecular pathways involved in this process are however still largely unknown. The numerous differences in the skin of the early fetus versus skin in later developmental stages might provide clues for the mechanisms of scarless healing. This review summarizes the differences between mammalian fetal skin and the skin at later developmental phases in healthy and wounded conditions, focusing on extracellular matrix components, which are crucial factors in the microenvironment that direct cells and tissue functions and hence the wound healing process.

Psoriasis is an immune-mediated inflammatory disorder, where the majority of the patients suffer from psoriasis capitis or scalp psoriasis. Current therapeutics remain ineffective to treat scalp lesions. In this study, we present a whole-metagenome characterization of the scalp microbiome in psoriasis capitis. We investigated how changes in the homeostatic cutaneous microbiome correlate with the condition and identified metagenomic biomarkers (taxonomic, functional, virulence factors, antimicrobial resistance genes) that could partly explain its emergence. Within this study, 83 top and back scalp samples from healthy individuals and 64 lesional and nonlesional scalp samples from subjects with untreated psoriasis capitis were analyzed. Using qPCR targeting the 16S and 18S ribosomal RNA genes, we found a significant decrease in microbial load within scalp regions affected by psoriasis compared with that in their nonlesional counterparts. Metagenomic analysis revealed that psoriatic lesions displayed significant lower Cutibacterium species (including C. modestum, C. namnetense, C. granulosum, C. porci), along with an elevation in Staphylococcus aureus. A heightened relative presence of efflux pump protein-encoding genes was detected, suggesting potential antimicrobial resistance mechanisms. These mechanisms are known to specifically target human antimicrobial peptides (including cathelicidin LL-37), which are frequently encountered within psoriasis lesions. These shifts in microbial community dynamics may contribute to psoriasis disease pathogenesis.

Skin in vitro models offer much promise for research, testing drugs, cosmetics, and medical devices, reducing animal testing and extensive clinical trials. There are several in vitro approaches to mimicking human skin behavior, ranging from simple cell monolayer to complex organotypic and bioengineered 3-dimensional models. Some have been approved for preclinical studies in cosmetics, pharmaceuticals, and chemicals. However, development of physiologically reliable in vitro human skin models remains in its infancy. This review reports on advances in in vitro complex skin models to study skin homeostasis, aging, and skin disease.

Numerous recent evidence highlights epidemiological connections between rosacea and metabolic disorders. However, the precise path through which metabolic factors impact rosacea risk is still unclear. Therefore, this study aims to investigate the role of adiponectin, a crucial adipokine that regulates metabolic homeostasis, in the pathogenesis of rosacea. We elucidated a detrimental feedback loop between rosacea-like skin inflammation and decreased levels of skin adiponectin. To elaborate, rosacea lesional skin exhibits diminished adiponectin expression compared with nonlesional areas in the same patients. Induction of rosacea-like inflammation reduced adiponectin levels in the skin by generating inflammatory cytokines that suppress adiponectin production from subcutaneous adipocytes. Conversely, complete depletion of adiponectin exacerbated rosacea-like features in the mouse model. Mechanistically, adiponectin deficiency led to heightened S6 phosphorylation, a marker of the mTORC1 signaling pathway, in the epidermis. Adiponectin significantly inhibited S6 phosphorylation in cultured keratinocytes. Notably, replenishing adiponectin whole protein or topically applying an agonist for adiponectin receptor 1 successfully improved rosacea-like features in mice. This study contributes to understanding the role of adiponectin in skin inflammation associated with rosacea pathophysiology, suggesting that restoring adiponectin function in the skin could be a potential therapeutic strategy.

Epidermal keratinocytes, immune cells, and sensory nerves all contribute to immune balance and skin homeostasis. Keratinocyte's release of GFs, neuromodulators, and immune activators is particularly important because each can evoke local (skin) and systemic (ie, immune and neural) responses that can initiate and exacerbate skin pathophysiology. From studies of skin and neural GFs, we hypothesized that neurturin (Nrtn), a member of the GDNF family that is expressed in the skin, has particular importance in this process. In this study, we examine how elevation of Nrtn in skin keratinocytes impacts early cytokine expression in response to complete Freund's adjuvant-mediated inflammation. Nrtn-overexpressing mice and wild-type mice injected with Nrtn exhibit an enhanced level of TNFα and IL-1β cytokines in the skin, a response previously shown to support healing. In vitro assays suggest that one source of the Nrtn-induced TNFα increase is keratinocytes, which are shown to express Nrtn and mRNAs encoding the Nrtn receptors GFRα2, Ret, ITGB1, and NCAM. These findings support the contribution of keratinocyte-derived Nrtn as an autocrine/paracrine factor that acts as a first-line defense molecule that regulates the initial cytokine response to inflammatory challenge.

Immunomodulatory agents have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting owing to poor pharmacokinetics and toxicity associated with systemic administration. Conversely, when locally delivered, immunomodulatory agents require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol-coated biodegradable nanoparticles (NPs) engineered for gradual drug release from the NP core, resulting in a more persistent stimulation of antitumor immune responses while minimizing systemic side effects. In a model of malignant melanoma, we demonstrate that hyperbranched polyglycerol-NP encapsulation significantly improves the antitumor efficacy of MPLA by enhancing its ability to remodel the tumor microenvironment. Relative to free MPLA, hyperbranched polyglycerol-coated NP-encapsulated MPLA significantly increased the NK cell- and cytotoxic T-cell-mediated antitumor immune response and tuned the tumor-draining lymph nodes toward a T helper 1 response. Furthermore, when combined with local delivery of a chemotherapeutic agent, hyperbranched polyglycerol-NP-MPLA induces the conversion of an immunosuppressive tumor microenvironment to immunogenic tumor microenvironment and significantly improves survival.