The Journal of investigative dermatology最新文献

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity.

Increasing resistance of dermatophytes against antifungals creates global public health problems, rendering essential a better understanding of virulence mechanisms and factors determining host specificity of dermatophytes. Because dermatophytes switch from a saprophytic to a parasitic lifestyle by reprogramming gene expression, reliable experimental models are needed to investigate the pathogenesis of dermatophytosis. In this study, a relevant mouse model of Trichophyton benhamiae dermatophytosis was assessed, together with a model based on reconstructed human epidermis, allowing their respective validation regarding fungal gene expressed during infection. The use of a standardized inoculum induced a natural-like superficial infection in mice. The severity and persistence of lesions enabled the assessment of infection markers, including mouse-specific proinflammatory molecules and fungal genes previously reported as potential virulence factors. Upregulated expression of fungal genes, including those encoding subtilisins, in infected reconstructed human epidermis revealed that dermatophytes deploy similar processes as those observed during in vivo infection. The reconstructed human epidermis model was then used to compare infections by anthropophilic Trubrum and zoophilic Tbenhamiae. Therefore, these 2 models represent complementary analytical tools to study the pathogenesis of acute dermatophytoses. In addition, we have identified certain fungal markers of infection and highlighted the existence of different mechanisms deployed by zoophilic versus anthropophilic dermatophytes.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized by multiple, intensely pruritic, distinctive nodular lesions. Subsequent scratching can further intensify the pruritus, culminating in a self-reinforcing itch-scratch cycle, which drives lesion development. The latest data indicate dysregulation of the neuroimmune axis in PN pathogenesis, including the involvement of sensory neurons, key effector immune cells, proinflammatory cytokines, dermal fibroblasts, and pruritogens. In this review, we highlight evidence supporting the role of type 2 immune axis dysregulation in driving the clinical presentation of PN and discuss how related signaling pathways may offer effective therapeutic targets to control PN signs and symptoms.

Acantholytic skin disorders, by definition, compromise intercellular adhesion between epidermal keratinocytes. The root cause of blistering in these diseases traces back to direct disruption of adhesive cell-cell junctions, exemplified by autoantibody-mediated attack on desmosomes in pemphigus. However, genetic acantholytic disorders originate from more indirect mechanisms. Darier disease and Hailey-Hailey disease arise from mutations in the endoplasmic reticulum calcium pump, SERCA2, and the Golgi calcium/manganese pump, SPCA1, respectively. Though the disease-causing mutations have been known for nearly 25 years, the mechanistic linkage between dysregulation of intracellular ion stores and weakening of cell-cell junctions at the plasma membrane remains puzzling. The molecular underpinnings of a related idiopathic disorder, Grover disease, are even less understood. Due to an incomplete understanding of acantholytic pathology at the molecular level, these disorders lack proven, targeted treatment options, leaving patients with the significant physical and psychological burdens of chronic skin blistering, infections, and pain. This article aims to review what is known at the molecular, cellular, and clinical levels regarding these under-studied disorders and to highlight knowledge gaps and promising ongoing research. Armed with this knowledge, our goal is to aid investigators in defining essential questions about disease pathogenesis and to accelerate progress toward novel therapeutic strategies.

Skin aging is a complex biological process affected by a plethora of intrinsic and extrinsic factors that alter cutaneous functions through the modulations of signaling pathways and responses. Expressed in various cell types and skin tissue layers, G protein-coupled receptors (GPCRs) play a vital role in regulating skin aging. We have cataloged 156 GPCRs expressed in the skin and reviewed their roles in skin aging, such as pigmentation, loss of elasticity, wrinkles, rough texture, and aging-associated skin disorders. By exploring the GPCRs found in the skin, it may be possible to develop new treatment regimens for aging-associated skin conditions using GPCR ligands.

Spatial transcriptomic (ST) profiling is the mapping of gene expression within cell populations with preservation of positional context and represents an exciting new approach to develop our understanding of local and regional influences upon skin biology in health and disease. With the ability to probe from a few hundred transcripts to the entire transcriptome, multiple ST approaches are now widely available. In this paper, we review the ST field and discuss its application to dermatology. Its potential to advance our understanding of skin biology in health and disease is highlighted through the illustrative examples of 3 research areas: cutaneous aging, tumorigenesis, and psoriasis.