This study establishes CD68, conventionally known as a macrophage marker, as a regulator of melanocyte biology. Using a human embryonic stem cell differentiation model that replicates neural crest-derived melanocyte deve...This study establishes CD68, conventionally known as a macrophage marker, as a regulator of melanocyte biology. Using a human embryonic stem cell differentiation model that replicates neural crest-derived melanocyte development, we performed single-cell RNA sequencing across 5 critical developmental time points (days 0, 6, 9, 11, and 25) to construct a comprehensive transcriptional atlas of melanocyte differentiation. Application of the single-cell orientation tracing algorithm revealed CD68 as a previously unrecognized component of melanogenesis, showing coordinated expression with core regulators, including MITF, TYR, and TYRP1. Functional validation demonstrated that CD68 knockdown significantly impairs melanin synthesis, cell proliferation, and MAPK pathway activation. Together, these findings redefine the biological significance of CD68 beyond its classical association with immune cells, identifying CD68 as a component of the melanogenic regulatory network. This work provides significant insights for understanding melanocyte development and highlights CD68 as a potential therapeutic target for pigmentary disorders.
Hidradenitis suppurativa is a chronic, debilitating inflammatory skin disease that progresses from superficial nodules in early stages to dermal tunnels, tertiary lymphoid structures, and fibrosis in advanced lesions. In...Hidradenitis suppurativa is a chronic, debilitating inflammatory skin disease that progresses from superficial nodules in early stages to dermal tunnels, tertiary lymphoid structures, and fibrosis in advanced lesions. Interplays between dermal tunnel keratinocytes, tertiary lymphoid structures, and fibroblasts promote pathogenic T-cell and B-cell inflammation in late-stage disease. However, whether these immune activations sequentially precede or follow late-stage structure formation is unclear. To delineate the temporal sequence of immune activation, we integrated spatial and single-cell transcriptomic analyses of early- and late-stage hidradenitis suppurativa and compared them with those of acne conglobata and psoriasis. Spatial transcriptomics of 156 regions of interest revealed robust dermal immune activation in early-stage hidradenitis suppurativa, including B-cell enrichment, type 17 T-cell pathway activation, and neutrophilic infiltration, occurring prior to tunnel or tertiary lymphoid structure formation. Single-cell RNA sequencing confirmed early plasma cell expansion and identified multifunctional B cells expressing proinflammatory cytokines, antigen-presentation machinery, and Igs. Notably, T cells rather than fibroblasts were the predominant producers of the B-cell chemoattractant CXCL13 in early lesions. Together, these findings demonstrate that hidradenitis suppurativa exhibits early and sustained immune activation that precedes dermal remodeling, underscoring the aggressive nature from its onset and suggesting that early therapeutic targeting of the type 17 T-cell axis and B-cell-mediated inflammation may help prevent disease progression.
Irie H, Nakashima C, Ishida Y
… +15 more, Kitayama N, Hirata M, Kataoka TR, Miyake T, Asahina R, Kogame T, Nakamizo S, Nakajima S, Egawa G, Nomura T, Takeuchi O, Kubo M, Kambe N, Otsuka A, Kabashima K
Tang AS, Wei ML, Haemel A
… +3 more, La C, Sirota M, Lee EY
J Invest Dermatol
· 2026 May · PMID 41689579
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Recent advances in artificial intelligence (AI) and multimodal data collection are revolutionizing dermatology. Generative AI and machine-learning approaches offer opportunities to enhance the diagnosis and treatment of...Recent advances in artificial intelligence (AI) and multimodal data collection are revolutionizing dermatology. Generative AI and machine-learning approaches offer opportunities to enhance the diagnosis and treatment of autoimmune and inflammatory skin diseases, including atopic dermatitis, psoriasis, hidradenitis suppurativa, vitiligo, alopecia areata, and rheumatic skin disease. This review examines the current landscape of AI applications for inflammatory skin diseases and explores how generative AI and machine-learning methods can advance the field through deep phenotyping, characterization of disease heterogeneity, drug discovery, precision medicine, and delivery of clinical care. We discuss the promises and challenges of these technologies and present a vision for their integration into clinical practice.
Köhling V, Peters F, Götting I
… +20 more, Fries E, Beck N, Armbrust F, Beckinger S, Bülck C, Canbay V, Harder I, Mengel M, Rüffer M, Bickenbach K, Kalogeropoulos K, Schweizer M, Lewerenz M, Schumacher N, Jonca N, Haase M, Naumann R, Auf dem Keller U, Becker-Pauly C, Rüffer S
Dysregulations within the epidermal proteolytic network can cause hyperproliferative and inflammatory disorders. Although the metalloprotease meprin α is localized in the stratum basale in healthy skin, increased levels...Dysregulations within the epidermal proteolytic network can cause hyperproliferative and inflammatory disorders. Although the metalloprotease meprin α is localized in the stratum basale in healthy skin, increased levels are found in the upper epidermal layers in wound healing and psoriatic lesions. To investigate a link between meprin α expression and keratinocyte proliferation, we developed a mouse model for inducible expression of pathological meprin α levels (ie, K5Mα mice). K5Mα mice developed a skin phenotype characterized by hyperkeratosis, acanthosis, parakeratosis, and barrier defect. Keratinocyte hyperproliferation and local inflammation were induced upon induction of meprin α expression. By N-terminomics, we identified dermokine, a regulator of keratinocyte proliferation and epidermal immune response, as a putative substrate of meprin α. We validated the proteolysis and identified the cleavage site, which is highly conserved in mammals, suggesting that dermokine degradation by meprin α represents a central mechanism in wound healing and hyperproliferative skin diseases.
The cutaneous vascular network, located in the skin dermis, plays vital roles in thermoregulation, immune surveillance, and tissue regeneration. Despite its important functions, the cutaneous vasculature remains an under...The cutaneous vascular network, located in the skin dermis, plays vital roles in thermoregulation, immune surveillance, and tissue regeneration. Despite its important functions, the cutaneous vasculature remains an understudied component of the skin. This article outlines approaches for intravital 2-photon microscopy to visualize and track vascular dynamics in mouse skin, particularly the hind paw, which offers a simplified, hairless model for longitudinal imaging. Utilizing genetically encoded fluorescent reporters, endothelial cells can be selectively and dynamically labeled to study vascular remodeling events that occur over the time frame of days to weeks, necessitating longitudinal approaches to capture the dynamics and resolution of these processes. Mosaic labeling approaches enable the tracking of single cells within the context of the remodeling network, allowing for an understanding of cellular behaviors that drive remodeling events. Intravital imaging also provides an opportunity to visualize and measure vascular function such as hemodynamics and barrier function. Collectively, these techniques provide powerful tools to dissect postnatal vascular development, adult homeostatic maintenance, and response to injury and holds potential for the interrogation of fundamental aspects of vascular biology as well as the understanding of cutaneous pathologies that involve the vasculature.
Keratinocyte migration is an integral part of epidermal development and homeostasis. Because of its complexity, no single experimental approach is sufficient to capture all aspects of cell migration. This review covers a...Keratinocyte migration is an integral part of epidermal development and homeostasis. Because of its complexity, no single experimental approach is sufficient to capture all aspects of cell migration. This review covers a range of strategies for studying keratinocyte migration in culture-based systems at different levels of complexity. First, single-cell migration experiments focus on the fundamental processes of cell locomotion. Second, monolayer migration experiments incorporate the influence of cell-cell adhesion and provide a simplified model of collective motion. Finally, epidermal organotypic culture migration experiments model collective migration in a 3-dimensional context closely mimicking the stratified squamous epidermal architecture, providing a bridge between tissue culture-based approaches and animal models. Key design principles of each model are discussed, and quantitative analysis methods for the rich datasets captured by these experiments are reviewed in detail.