Cutibacterium acnes (C. acnes) is a common skin commensal associated in acne pathogenesis. Here, we investigated whether acne-associated (HL043PA1, C) and healthy skin-associated (HL110PA3, C) C. acnes strains differenti...Cutibacterium acnes (C. acnes) is a common skin commensal associated in acne pathogenesis. Here, we investigated whether acne-associated (HL043PA1, C) and healthy skin-associated (HL110PA3, C) C. acnes strains differentially induce extracellular traps (ET) in human neutrophils (NETs) and Th17 cells (TETs) and defined their proteomic and functional properties. Both strains triggered rapid ET release from neutrophils and Th17 cells. However, whereas NETs displayed a conserved proteomic profile regardless of strain, TETs exhibited strain-specific specialization. C-induced TETs were enriched in inflammatory and extracellular matrix remodeling proteins, whereas C-induced TETs showed increased abundance of nuclear, mitochondrial, and antimicrobial proteins, including granulysin, granzyme B, and cathepsin C. Functional assays demonstrated that these compositional differences translate into distinct effector programs, with C-induced TETs mediating DNA-dependent antimicrobial activity against both C. acnes and Escherichia coli. Gene ontology analysis revealed that NETs and TETs share a core proteome, consistent with a conserved structural framework, whereas TETs exhibit greater functional specialization. Together, these findings reveal strain- and cell type-specific regulation of ET composition and function, suggesting that C-induced TETs may contribute to skin immune homeostasis, while C-induced TETs may promote inflammatory and tissue remodeling responses in acne.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with a poorly understood cell of origin and initiation process. Most MCC tumors feature monoclonal integration of Merkel cell polyomavirus (MC...Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with a poorly understood cell of origin and initiation process. Most MCC tumors feature monoclonal integration of Merkel cell polyomavirus (MCPyV) DNA, which expresses viral small T (sT-Ag) and large T antigens (LT-Ag), responsible for driving MCC tumors. The process by which MCPyV T antigens (T-Ags) transform cells to initiate MCC has been unclear, in part due to the lack of physiologically relevant in vivo models. Building upon our previous work, which demonstrated that SOX9-expressing (SOX9+) hair follicle Merkel cell progenitors are susceptible to T-Ag-mediated reprogramming, we establish a mouse model in which sT-Ag expression and Trp53 attenuation in SOX9 cells produce metastatic neuroendocrine tumors with histopathologic and immunophenotypic features of human MCC. Importantly, while sT-Ag alone induces partial MCC-associated gene expression, suppression of p53 is required for sT-Ag to induce neuroendocrine lineage transdifferentiation in the hair follicle. Cumulatively, these studies enhance our knowledge of MCC biology and establish a de novo MCC tumorigenesis model in a tractable immunocompetent system that will be invaluable for further advancements in the field.
Biallelic ITGA3 variants cause a rare subtype of junctional epidermolysis bullosa named interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB). ILNEB is characterized by extensive clinical heter...Biallelic ITGA3 variants cause a rare subtype of junctional epidermolysis bullosa named interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB). ILNEB is characterized by extensive clinical heterogeneity, suggesting the existence of modifier genes. We studied a family with two siblings affected with ILNEB due to a homozygous ITGA3 variant. The disease severity was strikingly different in the two siblings. Whole exome sequencing revealed the presence of two different heterozygous variants in ITGB4 in each of the two patients: p.Arg977Cys in the more severely affected individual and p.Asp285Asn in the milder case. Accordingly, the ITGB4 p.Arg977Cys variant caused a significantly greater reduction in ITGB4 membrane localization compared to the p.Asp285Asn variant. In addition, the ITGB4 p.Arg977Cys variant resulted in significantly diminished activation of the FAK/AKT/mTOR/S6 pathway as compared with the p.Asp285Asn variant. Finally, using co-immunoprecipitation assays as well as confirmatory proximity ligation assays, we identified an hitherto unrecognized direct interaction between ITGA3 and ITGB4 which was more significantly compromised by the ITGB4 p.Arg977Cys than by the p.Asp285Asn variant. Our findings indicate that monoallelic ITGB4 genetic variants may modulate the severity of ITGA3-associated ILNEB.
Alopecia areata (AA) is a chronic autoimmune disease characterized by sudden patchy hair loss and persistent inflammation. To date, only JAK inhibitors have been approved for AA treatment, but FDA-issued black box warnin...Alopecia areata (AA) is a chronic autoimmune disease characterized by sudden patchy hair loss and persistent inflammation. To date, only JAK inhibitors have been approved for AA treatment, but FDA-issued black box warnings highlight the need for alternative therapies. We previously reported that an anti-γc antibody, hC2, inhibits autoreactive B, T, and NK cells by selectively attenuating JAK/STAT signaling induced by six γc cytokines, without affecting off-target TEC kinase pathways. Here, we sought to define the mechanism of action and efficacy of hC2 in AA by using an ex-vivo T cell platform and a xenogeneic AA-like mouse model induced by human T cell engraftment. Analyses showed that hC2 could restore hair follicle homeostasis and suppress hair loss by inhibiting autoreactive T cell activity and proliferation of tissue-resident memory T cells. Although JAK3 inhibitor ritlecitinib could potentially protect hair follicles through T cell depletion strategy in-vitro, severe side effects were associated with ritlecitinib treatment while no significant safety issues were noted after hC2 treatment in the xenogeneic AA-like mouse model. These findings suggest that hC2 might offer a safer and more effective therapeutic approach for AA patients in the future.
KCTD1 and KCTD15 form pentameric complexes that regulate neural crest cell (NCC) and keratinocyte functions, and dominant-negative mutations in their genes cause aplasia cutis congenita (ACC) and craniofacial abnormaliti...KCTD1 and KCTD15 form pentameric complexes that regulate neural crest cell (NCC) and keratinocyte functions, and dominant-negative mutations in their genes cause aplasia cutis congenita (ACC) and craniofacial abnormalities. Although KCTD1/KCTD15 complexes have been proposed to modulate multiple developmental pathways in vitro, the key downstream mechanisms responsible for these phenotypes in vivo remain unclear. Here, we investigated the function of KCTD1/KCTD15 complexes specifically in NCCs. Using conditional mouse models, cell lineage tracing, and genetic epistasis approaches, we show that KCTD1/KCTD15 complexes regulate NCC-dependent craniofacial development and midline scalp skin formation primarily by repressing the transcriptional activity of AP-2α and AP-2β. Loss of KCTD1/KCTD15 in NCCs resulted in ACC, cranial suture abnormalities, nasal bone hypoplasia, incisor agenesis, eyelid defects, pigmentation abnormalities, and cleft palate. Genetic reduction of AP-2α and AP-2β dosage in NCCs lacking KCTD1/KCTD15 markedly rescued these defects, establishing derepressed AP-2 activity as the principal pathogenic mechanism. Conversely, NCC-specific loss of AP-2α/AP-2β produced partially overlapping craniofacial defects, demonstrating that craniofacial morphogenesis is highly sensitive to AP-2 dosage. These findings identify a KCTD1/KCTD15-AP-2 regulatory axis as a central mechanism controlling neural crest-derived craniofacial development and scalp skin formation and establish ACC as a neurocristopathy arising from dysregulated AP-2 activity.
Acne vulgaris is one of the most common skin diseases around the world, affecting approximately 9.4% of the global population annually. Cellular and animal-based sebaceous gland models are widely employed to elucidate th...Acne vulgaris is one of the most common skin diseases around the world, affecting approximately 9.4% of the global population annually. Cellular and animal-based sebaceous gland models are widely employed to elucidate the pathophysiology and mechanisms behind acne. However, non-human animals do not develop acne, nor do they harbor Cutibacterium acnes as a commensal. Furthermore, cellular models are not the best as they cannot recapitulate progenitor-like characteristics of a sebaceous gland. Hence, there is a growing interest in sebaceous gland organoids (SGOs), which recapitulate the growth and differentiation of the gland. Here, we briefly review published SGOs protocols and describe our own model of "sebonoids." We discuss the advantages and disadvantages of various SGOs and provide a detailed protocol for generating our version.
Gross L, Buddenkotte J, Joy F
… +12 more, Jochebeth A, Leo R, Therachiyil L, Al-Marri F, Al-Dehneem R, Al Chalabi R, Elzouki AN, Sukik A, Al-Khawaga S, AlHammadi A, Schenk M, Steinhoff M
Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperproliferation and immune dysregulation. However, local metabolic interactions remain incompletely understood, and biomarkers for dis...Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperproliferation and immune dysregulation. However, local metabolic interactions remain incompletely understood, and biomarkers for disease activity and treatment response are still lacking. Current approaches such as skin biopsies or tape stripping are disruptive to the skin barrier and may cause scarring, limiting their repeated use. In contrast, microdialysis enables minimally invasive sampling of soluble mediators from intact skin. We applied untargeted proteomic and metabolomic profiling of skin microdialysates from lesional and nonlesional sites in patients with psoriasis and healthy controls to explore local pathophysiology and evaluate this technique's potential for monitoring disease severity and treatment response. Principal component analysis revealed distinct molecular signatures in psoriatic lesions, with separation by disease severity, resulting from elevated proinflammatory proteins (SERPINB3/4, FABP5), purine and pyrimidine metabolites (adenosine-5-monophosphate, 5'-cytidine monophosphate) and polyamines (spermidine and spermine). Pathway analysis confirmed upregulated nucleotide metabolism and polyamine biosynthesis alongside reduced histidine metabolism, consistent with hyperproliferation, immune activation, and barrier disruption. Importantly, lesional metabolomic profiles normalized in patients responding to systemic therapy, highlighting the utility of microdialysate profiling for tracking therapeutic efficacy. This study establishes microdialysate proteometabolomics as a minimally invasive platform for mechanistic studies, biomarker discovery, and personalized monitoring in psoriasis.
Cutaneous T-cell lymphomas, namely mycosis fungoides and Sézary syndrome, arise through a complex interplay of genetic alterations, epigenetic deregulation, immune imbalance, and tumor-microenvironment interactions. A pr...Cutaneous T-cell lymphomas, namely mycosis fungoides and Sézary syndrome, arise through a complex interplay of genetic alterations, epigenetic deregulation, immune imbalance, and tumor-microenvironment interactions. A progressive T helper 1-to-T helper 2 shift and chemokine-directed trafficking promote immune evasion and sustained malignant T-cell activity, whereas emerging data show subclonal diversity enabling adaptation to microenvironmental and therapeutic pressures. Skin-resident immune cells further shape disease behavior, and Staphylococcus aureus superantigens act as microenvironmental amplifiers that enhance malignant signaling and contribute to treatment resistance. A deeper understanding of how these molecular, immunological, and microbiome factors converge is essential to develop more precise, biomarker-informed therapeutic strategies.
Artificial intelligence (AI) is reshaping dermatology through diagnostic image analysis, clinical documentation, and patient communication tools. However, AI's environmental costs remain largely invisible to clinicians....Artificial intelligence (AI) is reshaping dermatology through diagnostic image analysis, clinical documentation, and patient communication tools. However, AI's environmental costs remain largely invisible to clinicians. Because training large AI models requires substantial energy, data center electricity use has risen alongside AI adoption, and cooling AI infrastructure centers increases water demand. These environmental burdens disproportionately affect resource-constrained communities. This creates an urgent priority for dermatology. Climate change directly threatens dermatologic health through global warming, increased UV exposure, air pollution, microplastics, expanded ranges of infectious dermatoses, exacerbation of inflammatory dermatoses, and more. The American Dermatological Association's 2025 Policy Statement on Climate Change commits the specialty to environmental stewardship. Accordingly, AI implementation must align with this commitment, not undermine it. Dermatology can minimize AI's environmental footprint through the following strategic choices: selecting computationally efficient models, sharing datasets to eliminate redundant training, implementing AI selectively where clinical benefit justifies environmental cost, and partnering with vendors committed to transparent reporting. Professional organizations can establish sustainability standards, require environmental impact reporting in research, and advocate for regulatory frameworks mandating vendor accountability. By demonstrating that technological innovation and climate responsibility are compatible goals, dermatology can serve as a model for sustainable AI integration across medical specialties.
Hou P, Che Y, Han J
… +14 more, Deming C, Amirkhani A, Kim CS, Taylor ME, Velez D, Cho E, Holmes CJ, Suh G, Castelo-Soccio L, NISC Comparative Sequencing Program, McDermott DH, Murphy PM, Segre JA, Kong HH
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare inborn error of immunity (IEI) caused by hyperfunctional pathogenic variants in CXC chemokine receptor 4 (CXCR4), predisposing individ...Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare inborn error of immunity (IEI) caused by hyperfunctional pathogenic variants in CXC chemokine receptor 4 (CXCR4), predisposing individuals to recurrent bacterial skin and airway infections and warts. The targeted CXCR4 antagonist plerixafor has shown efficacy in wart regression and potential reduction in bacterial infection frequency. Here, we investigated skin microbiomes of 11 patients with WHIM syndrome using shotgun metagenomics, compared to healthy controls. WHIM skin microbial communities displayed greater inter-individual variability, with highly diverse human papillomavirus profiles and expansion of airway-associated pathogens on the skin. Among patients receiving plerixafor therapy, we observed shifts in the viral composition and a downward trend in viral abundances. Together, these findings demonstrate the distinctive and permissive skin microbiome in WHIM syndrome and highlight the potential microbiome-modulating effects of targeted CXCR4 antagonism.