The 50 most-cited articles in Journal of Investigative Dermatology, 2024

The function of keratinocytes (KCs) to form a barrier and produce cytokines is well-known, but recent progress has revealed many different roles for KCs in regulation of skin immunity. In this review, we provide an update on the current understanding of how KCs communicate with microbes, immunocytes, neurons, and other cells to form an effective immune barrier. We catalog the large list of genes and metabolites of KCs that participate in host defense and discuss the mechanisms of immune crosstalk, addressing how KCs simultaneously form a physical barrier, communicate with fibroblasts, and control immune signals. Overall, the signals sent and received by KCs are an exciting group of therapeutic targets to explore in the treatment of dermatologic disorders.

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.

Skin-on-a-chip (SoC) technologies are emerging as a paradigm shift in dermatology research by replicating human physiology in a dynamic manner not achievable by current animal models. Although animal models have contributed to successful clinical trials, their ability to predict human outcomes remains questionable, owing to inherent differences in skin anatomy and immune response. Covering areas including infectious diseases, autoimmune skin conditions, wound healing, drug toxicity, aging, and antiaging, SoC aims to circumvent the inherent disparities created by traditional models. In this paper, we review current SoC technologies, highlighting their potential as an alternative to animal models for a deeper understanding of complex skin conditions.

Wound healing is a dynamic process over temporal and spatial scales. Key to repair outcomes are fibroblasts; yet, how they modulate healing across time and in different wound regions remains incompletely understood. By integrating single-cell RNA-sequencing datasets of mouse skin and wounds, we infer that fibroblasts are the most transcriptionally dynamic skin-resident cells, evolving during postnatal skin maturation and rapidly after injury toward distinct late scar states. We show that transcriptional dynamics in fibroblasts are largely driven by genes encoding extracellular matrix and signaling factors. Lineage trajectory inference and spatial gene mapping reveal that Prg4-expressing fibroblasts transiently emerge along early wound edges. Within days, they become replaced by long-lasting and likely noninterconverting fibroblast populations, including Col25a1-expressing and Pamr1-expressing fibroblasts that occupy subepidermal and deep scar regions, respectively, where they engage in reciprocal signaling with immune cells. Signaling inference shows that fibroblast-immune crosstalk…

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.

UVR is a skin carcinogen, yet no studies link sun exposure to increased all-cause mortality. Epidemiological studies from the United Kingdom and Sweden link sun exposure with reduced all-cause, cardiovascular, and cancer mortality. Vitamin D synthesis is dependent on UVB exposure. Individuals with higher serum levels of vitamin D are healthier in many ways, yet multiple trials of oral vitamin D supplementation show little benefit. Growing evidence shows that sunlight has health benefits through vitamin D-independent pathways, such as photomobilization of nitric oxide from cutaneous stores with reduction in cardiovascular morbidity. Sunlight has important systemic health benefit as well as risks.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients…

In an aging society with common lifestyle-associated health issues such as obesity and diabetes, chronic wounds pose a frequent challenge that physicians face in everyday clinical practice. Therefore, nonhealing wounds have attracted much scientific attention. Several in vitro and in vivo models have been introduced to deepen our understanding of chronic wound pathogenesis and amplify therapeutic strategies. Understanding how wounds become chronic will provide insights to reverse or avoid chronicity. Although choosing a suitable model is of utmost importance to receive valuable outcomes, an ideal in vivo model capturing the complexity of chronic wounds is still missing and remains a translational challenge. This review discusses the most relevant mammalian models for wound healing studies and provides guidance on how to implement the hallmarks of chronic wounds. It highlights the benefits and pitfalls of established models and maps out future avenues for research.

All layers and appendages of the skin are densely innervated by afferent and efferent neurons providing sensory information and controlling skin perfusion and sweating. In mice, neuronal functions have been comprehensively linked to unique single-cell expression patterns and to characteristic arborization of nerve endings in skin and dorsal horn, whereas for humans, specific molecular markers for functional classes of afferent neurons are still lacking. Moreover, bidirectional communication between sensory neurons and local skin cells has become of particular interest, resulting in a broader physiological understanding of sensory function but also of trophic functions and immunomodulation in disease states.

Epithelial and immune cells have long been appreciated for their contribution to the early immune response after injury; however, much less is known about the role of mesenchymal cells. Using single-nuclei RNA sequencing, we defined changes in gene expression associated with inflammation 1 day after wounding in mouse skin. Compared with those in keratinocytes and myeloid cells, we detected enriched expression of proinflammatory genes in fibroblasts associated with deeper layers of the skin. In particular, SCA1+ fibroblasts were enriched for numerous chemokines, including CCL2, CCL7, and IL-33, compared with SCA1- fibroblasts. Genetic deletion of Ccl2 in fibroblasts resulted in fewer wound-bed macrophages and monocytes during injury-induced inflammation, with reduced revascularization and re-epithelialization during the proliferation phase of healing. These findings highlight the important contribution of fibroblast-derived factors to injury-induced inflammation and the impact of immune cell dysregulation on subsequent tissue repair.

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.

TRIAL DESIGN: Pemphigus is a rare but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. METHODS: Adults (aged 18-80 years) were randomized 1:1 to 400 mg rilzabrutinib (n = 65) or placebo (n = 66) twice daily (with CS ≤ 0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/pemphigus foliaceus. RESULTS: The primary endpoint of complete remission from week 29 to week 37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13 of 54 (24%) rilzabrutinib versus 10 of 55 (18%) placebo patients with PV (P = .45). Secondary endpoints showed numerical but nonsignificant improvements with rilzabrutinib (vs placebo) in reduced CS use, prolonged complete remission duration, and faster time to first complete remission. CONCLUSIONS: Overall, rilzabrutinib was…

Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins of itch are complex, and it is considered both a defense mechanism and a cause of disease that leads to inflammation and psychological stress. Considerable progress has been made in understanding the processes that trigger itch, particularly the pruritoceptive origins that are generated in the skin. This perspective review discusses the implications of a recent observation that the V8 protease expressed by Staphylococcus aureus can directly trigger sensory neurons in the skin through activation of protease-activated receptor 1. This may be a key to understanding why itch is so common in AD because S. aureus commonly overgrows in this disease owing to deficient antimicrobial defense from both the epidermis and the cutaneous microbiome. Increased understanding of the role of microbes in AD provides increased opportunities for safely improving the treatment of this disorder.

Our skin is home to a diverse community of commensal microorganisms integral to cutaneous function. However, microbial dysbiosis and barrier perturbation increase the risk of local and systemic infection. Staphylococcus aureus is a particularly problematic bacterial pathogen, with high levels of antimicrobial resistance and direct association with poor healing outcome. Innovative approaches are needed to selectively kill skin pathogens, such as S aureus, without harming the resident microbiota. In this study, we provide important data on the selectivity and efficacy of an S aureus-targeted endolysin (XZ.700) within the complex living skin/wound microbiome. Initial cross-species comparison using Nanopore long-read sequencing identified the translational potential of porcine rather than murine skin for human-relevant microbiome studies. We therefore performed an interventional study in pigs to assess the impact of endolysin administration on the microbiome. XZ.700 selectively inhibited endogenous porcine S aureus in vivo, restoring microbial diversity and promoting multiple aspects of…

The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensal Staphylococcus epidermidis is protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. In this study, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. Although depletion of the skin microbiome through antibiotics delayed repair from damage, probiotic-like application of commensals-including the mouse commensal Staphylococcus xylosus, 3 distinct isolates of S. epidermidis, and all other tested human skin commensals-also significantly delayed barrier repair. Increased inflammation was observed within 4 hours of S. epidermidis exposure and persisted through day 4, at which point the skin displayed a chronic wound-like inflammatory state with increased neutrophil infiltration,…

Macroscopic loss of extracellular matrix can lead to chronic defects in skin wound healing, but supplementation of extracellular matrix holds promise for facilitating wound closure, particularly in diabetic wound healing. We recently showed that the extracellular matrix proteoglycan agrin accelerates cutaneous wound healing by improving mechanoperception of migrating keratinocytes and allowing them to respond to mechanical stresses through matrix metalloproteinase 12 (MMP12). RNA-sequencing analysis revealed that in addition to a disorganized extracellular matrix, agrin-depleted skin cells have impaired YAP/TAZ transcriptional outcomes, leading us to hypothesize that YAP/TAZ, as central mechanosensors, drive the functionality of agrin-MMP12 signaling during cutaneous wound repair. In this study, we demonstrate that agrin activates YAP/TAZ during migration of keratinocytes after wounding in vitro and in vivo. Mechanistically, YAP/TAZ sustain agrin and MMP12 protein expression during migration after wounding through positive feedback. YAP/TAZ silencing abolishes agrin-MMP12-mediated…

Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage-specific antigen gp100 on HLA-A∗02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator's choice (n = 126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced, and expression of melanocytic genes decreased, whereas gene expression related to immunity and cytokine signaling increased. When adjusted for baseline prognostic features, patients with rash within…

Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from endoplasmic reticulum to membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like ER kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway, then tested the chemotactic migration of CD8 + T cells or CD11c + CD86 + cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8 + T cells in vitiligo. Additionally, dendritic cells from vitiligo patients…

Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3, which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. In this study, we provide evidence that EGFR inhibition by erlotinib ameliorates pemphigus vulgaris IgG-induced acantholysis in intact human epidermis. Pemphigus vulgaris IgG caused phosphorylation of EGFR (Y845) and Rous sarcoma-related kinase in human epidermis. In line with this, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and Rous sarcoma-related kinase family kinase signaling in response to pemphigus vulgaris IgG but not to pemphigus foliaceus autoantibodies. Erlotinib inhibited pemphigus vulgaris IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes, as well as ultrastructural alterations of desmosome size, plaque symmetry, and keratin filament insertion and restored the desmosome midline considered as hallmark of…

Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. In this study, we report results from a genome-wide meta-analysis of AD in 37,541 cases and 1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci, of which 10 were, to our knowledge, previously unreported. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD and of early- and late-onset AD, with data from the FinnGen project. Fifty-five of the 79 tested variants in the associated loci showed larger effect estimates for severe than for mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlie the development of new therapeutic strategies.

Dupilumab, a mAb targeting the IL-4Rα subunit, emerged in 2017 as a promising intervention for atopic dermatitis (AD). Three clinical trials led to dupilumab’s approval; no patients were diagnosed with lymphoma or cutaneous lymphoma during these trials (Blauvelt et al, 2017; Simpson et al, 2016). However, an increasing number of case reports have described biopsy-proven cutaneous T-cell lymphoma (CTCL) diagnosis or exacerbation after dupilumab initiation (Park et al, 2023; Visconti et al, 2023).

Roflumilast, the third phosphodiesterase-IV (PDE4) inhibitor approved for use in dermatology, is indicated for topical treatment of psoriasis, seborrheic dermatitis, and atopic dermatitis, whereas its 2 predecessors, apremilast and crisaborole, are indicated for oral treatment of psoriasis and topical treatment of atopic dermatitis, respectively. All 3 are rationally designed PDE4 inhibitors, but roflumilast is the most potent and effective among the 3, with in vitro inhibitory constant half-maximal inhibitory concentration value of 0.7 nM (roflumilast), 0.14 μM (apremilast), and 0.24 μM (crisaborole), representing differences of over 3 orders of magnitude. PDE4 is a cAMP (an intracellular secondary messenger) hydrolase consisting of at least 4 subtypes of exon-spliced isoforms, which are primarily expressed in immune cells for inflammatory response. PDE4 inhibition lengthens the duration of cAMP signals and increases cellular cAMP concentrations, generating anti-inflammatory effects. We examined the physicochemical principles that make PDE4 inhibitors effective and propose chemical…

In the skin, melanin is synthesized by melanocytes within melanosomes and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of UVR. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning through lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo, and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This…