Implications for cumulative and prolonged clinical improvement induced by cross-linked hyaluronic acid: An in vivo biochemical/microscopic study in humans.

In photoaged human skin, type I collagen fragmentation impairs dermal extracellular matrix (ECM) integrity, resulting in collapsed/contracted fibroblasts with reduced type I procollagen synthesis. Injections of cross-linked hyaluronic acid (CL-HA) reverse these deleterious changes. To investigate the time course and effects of biochemical changes induced by injected CL-HA, particularly whether fibroblast activation leads to accumulation/deposition of dermal collagen, we injected CL-HA into photoaged skin of human participants over 60 years-old and performed biochemical/microscopic analyses of skin samples.

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci.

Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis.

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2 fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state.

Skin aging from the perspective of dermal fibroblasts: the interplay between the adaptation to the extracellular matrix microenvironment and cell autonomous processes.

This article summarizes important molecular mechanisms that drive aging in human skin from the perspective of dermal fibroblasts. The dermis comprises the bulk of the skin and is largely composed of a collagen-rich extracellular matrix (ECM). The dermal ECM provides mechanical strength, resiliency, and an environment that supports the functions of ibroblasts and other types of dermal cells.

Keratinocytes sense and eliminate CRISPR DNA through STING/IFN-κ activation and APOBEC3G induction.

CRISPR/Cas9 has been proposed as a treatment for genetically inherited skin disorders. Here we report that CRISPR transfection activates STING-dependent antiviral responses in keratinocytes, resulting in heightened endogenous interferon (IFN) responses through induction of IFN-κ, leading to decreased plasmid stability secondary to induction of the cytidine deaminase gene APOBEC3G. Notably, CRISPR-generated KO keratinocytes had permanent suppression of IFN-κ and IFN-stimulated gene (ISG) expression, secondary to hypermethylation of the IFNK promoter region by the DNA methyltransferase DNMT3B.

Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin.

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin, including thinning, fragility, impaired wound healing, and a propensity for carcinoma. Matrix metalloproteinase-1 (MMP1) initiates the cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin.

Negative perceptions and emotional impact of striae gravidarum among pregnant women.

Background: The impact of striae gravidarum (SG), or stretch marks of pregnancy, on quality of life (QoL) is unclear.

Objective: The purpose of this study was to investigate how SG affect QoL in pregnant women.

Methods: In this cross-sectional survey study of healthy pregnant women who developed SG during their current pregnancy, we asked about the impact of lesions on emotional, psychological, and life-quality facets.

Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide.

Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genomewide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman ρ = 0.78; < 2 × 10).

Noninvasive Tape-Stripping with High-Resolution RNA Profiling Effectively Captures a Preinflammatory State in Nonlesional Psoriatic Skin.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis.

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

Background: A major issue with the current management of psoriasis is our inability to predict treatment response.

Objective: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis.

Methods: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples.

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis.

Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis.

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture.

Rejuvenation of Aged Human Skin by Injection of Cross-linked Hyaluronic Acid.

Background: Dermal injection of chemically cross-linked hyaluronic acid (CL-HA) is a common procedure to smooth wrinkles and add fullness to the face. Due to its physical properties, CL-HA both fills space and exerts mechanical forces within the dermis. Dermal fibroblasts produce the collagen-rich extracellular matrix (ECM), which comprises the bulk of skin.

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS.

Dermal Fibroblast CCN1 Expression in Mice Recapitulates Human Skin Dermal Aging.

The aging process deleteriously alters the structure and function of dermal collagen. These alterations result in thinning, fragility, wrinkles, laxity, impaired wound healing, and a microenvironment conducive to cancer. However, the key factors responsible for these changes have not been fully elucidated, and relevant models for the study of skin aging progression are lacking.

CD26 Identifies a Subpopulation of Fibroblasts that Produce the Majority of Collagen during Wound Healing in Human Skin.

Fibroblasts produce collagens and other proteins that form the bulk of the extracellular matrix (ECM) in connective tissues. Emerging data point to functional heterogeneity of fibroblasts. However, the lack of subtype-specific markers hinders our understanding of the different roles of fibroblasts in ECM biology, wound healing, diseases, and aging.

IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response.

Integrative Approach to Reveal Cell Type Specificity and Gene Candidates for Psoriatic Arthritis Outside the MHC.

We recently conducted a large association analysis to compare the genetic profiles between patients with psoriatic arthritis (PsA) and cutaneous-only psoriasis (PsC). Despite including over 7,000 genotyped patients, only the MHC achieved genome-wide significance. In this study, we hypothesized that appropriate epigenomic elements (H3K27ac marks for active enhancers) can guide us to reveal valuable information about the loci with suggestive evidence of association.

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity.

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women.

Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.

Objective: Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin.

Methods: mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin.

Physical properties of the photodamaged human skin dermis: Rougher collagen surface and stiffer/harder mechanical properties.

Fragmentation of collagen fibrils and aberrant elastic material (solar elastosis) in the dermal extracellular matrix (ECM) is among the most prominent features of photodamaged human skin. These alterations impair the structural integrity and create a dermal microenvironment prone to skin disorders. The objective of this study was to determine the physical properties (surface roughness, stiffness and hardness) of the dermal ECM in photodamaged and subject-matched sun-protected human skin.