Published papers

Host-microbe interactions orchestrate skin homeostasis, the dysregulation of which has been implicated in chronic inflammatory conditions such as atopic dermatitis and psoriasis. Here, we show that Staphylococcus cohnii is a skin commensal capable of beneficially inhibiting skin inflammation. We find that Tmem79−/− mice spontaneously develop interleukin-17 (IL-17)-producing T-cell-driven skin inflammation. Comparative skin microbiome analysis reveals that the disease activity index is negatively associated with S. cohnii. Inoculation with S. cohnii strains isolated from either mouse or human skin microbiota significantly prevents and ameliorates dermatitis in Tmem79−/− mice without affecting pathobiont burden. S. cohnii colonization is accompanied by activation of host glucocorticoid-related pathways and induction of anti-inflammatory genes in the skin and is therefore effective at suppressing inflammation in diverse pathobiont-independent dermatitis models, including chemically induced, type 17, and type 2 immune-driven models. As such, S. cohnii strains have great potential as effective live biotherapeutics for skin inflammation.

The skin plays a vital role in serving as a physical and immunologic barrier against external insults while orchestrating complex immune responses. Autoimmune skin diseases including pemphigus, vitiligo, and alopecia areata illustrate the intricate interplay between antigen-specific immunity and tissue-specific pathologies. Pemphigus serves as a model to understand the dynamics of peripheral immune tolerance and the interplay between humoral and cellular autoimmunity, emphasizing the role of regulatory T cells in controlling autoreactive responses. Similarly, vitiligo and alopecia areata highlight the pathological contribution of resident memory CD8+ T cells and IFN-γ signaling, identifying potential therapeutic targets such as the IL-15 signaling pathway to address disease intractability. In addition to autoimmune mechanisms, the skin microbiota profoundly influences local and systemic immune responses. Commensals such as Staphylococcus epidermidis promote homeostasis by regulating barrier integrity, T-cell activation, and wound repair, while dysbiosis exacerbates immune dysregulation. Innovative strategies, including the use of genetically modified microorganisms to stimulate antigen-specific immunity, hold promise for next-generation therapies. This review underscores the significance of antigen-specific immunity in skin diseases and the emerging role of microbiota in modulating immune responses. Future research into these areas is pivotal for advancing targeted therapies and understanding the interconnectedness of skin health and systemic immunity.

Immune responses are influenced by not only immune cells but also the tissue microenvironment where these cells reside. Recent advancements in understanding the underlying molecular mechanisms and structures of the epidermal tight junctions (TJs) and stratum corneum (SC) have significantly enhanced our knowledge of skin barrier functions. TJs, located in the granular layer of the epidermis, are crucial boundary elements in the differentiation process, particularly in the transition from living cells to dead cells. The SC forms from dead keratinocytes via corneoptosis and features three distinct pH zones critical for barrier function and homeostasis. Additionally, the SC-skin microbiota interactions are crucial for modulating immune responses and protecting against pathogens. In this review, we explore how these components contribute both to healthy and disease states. By targeting the skin barrier in therapeutic strategies, we can enhance its integrity, modulate immune responses, and ultimately improve outcomes for patients with inflammatory skin conditions.

Background: Cutaneous polyarteritis nodosa (cPN) is a necrotizing arteritis of medium-sized vessels limited to the skin. Because of its rarity and the diversity of its clinical manifestations, there is no consensus treatment. Moreover, there are no established indicators that predict disease severity or its outcome. Objectives: To investigate clinicolaboratory features that predict patients requiring systemic therapy, including corticosteroids, to control disease activity. Methods: Thirty-six patients with cPN who had not received systemic corticosteroids at their initial visit were retrospectively analysed by correlating the treatment and its response with clinicolaboratory findings. Results: The major medications administered were antiplatelet agents [64% (23/36)], vasodilators [39% (14/36)] and prednisolone (PSL) [36% (13/36)]. In total, 23 patients achieved remission without PSL, 5 were managed with compression therapy alone or even observation and 18 received antiplatelet monotherapy or combined with vasodilator/dapsone whereas 13 required PSL. Of the 13 who required PSL, 10 achieved remission with PSL monotherapy or PSL and single/multiple medications and 3 with PSL and multiple drugs then failed to achieve remission and underwent limb amputation. There were more skin ulcers and an elevated peripheral white blood cell (WBC) count and erythrocyte sedimentation rate (ESR) before corticosteroid induction in patients requiring PSL. Three patients with treatment failure had a markedly elevated ESR (> 50 mm h-1). Conclusions: More than half of patients with cPN can achieve remission without corticosteroids. An elevated WBC, an elevated ESR and the presence of skin ulcers predict the need for PSL. A high ESR before corticosteroid induction predicts treatment resistance, even with PSL.

During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcusargenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%–22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4+ and CD8+ T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. SargEY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. SargEY and SEY may play roles in exacerbating the respective toxin-producing strains in AD.

Nagashima-type palmoplantar keratosis (also referred to as SERPINB7 -related palmoplantar epidermal differentiation disorder) is the most common form of palmoplantar keratoderma in East Asia. It is characterized by erythematous hyperkeratosis, palmoplantar hyperhidrosis, and a distinctive foot odor that significantly impairs QOL. In this study, we aimed to clarify the etiology of this odor by investigating the plantar microbiome and evaluating the therapeutic effects of topical benzoyl peroxide. Compared with healthy controls, individuals with Nagashima-type palmoplantar keratosis exhibited significantly higher objective odor scores; increased bacterial load, especially in the intertoe area; and reduced microbial diversity. Corynebacterium and Staphylococcus were the predominant dysbiotic flora species. The topical application of benzoyl peroxide significantly reduced foot odor and bacterial load; increased microbial diversity; and selectively decreased Corynebacterium abundance, particularly that of C tuberculostearicum . These changes correlate with the species-specific susceptibility of skin-resident bacteria to benzoyl peroxide. Our findings suggest that microbial dysbiosis, especially the overgrowth of Corynebacterium species, is central to the pathogenesis of foot odor in Nagashima-type palmoplantar keratosis. Topical benzoyl peroxide is a promising therapeutic intervention for mitigating dysbiosis and its associated foot odor. This study highlights the potential of microbiome-targeted therapies for symptom relief in inherited skin disorders such as Nagashima-type palmoplantar keratosis.

We report a familial case of recurrent furunculosis caused by Panton-Valentine leukocidin (PVL)-positive community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in Tokyo. The index case, a 34-year-old female, and her family members (her husband and their 8-month-old son) were also affected, and all recovered after treatment with oral clindamycin, intranasal mupirocin, and hygiene interventions. Whole-genome sequencing revealed that five isolates from skin and nasal swabs belonged to ST8-IVa-t304, carrying ACME type I and PVL genes. All isolates were resistant to levofloxacin but susceptible to other anti-MRSA agents. Genomic analysis showed the absence of the SaPI5 island and the sek/seq genes. Based on phylogenetic analysis, we concluded that these strains represent a unique USA300-like sublineage that diverged from the closest USA300-NAE lineage. The USA300 clone has emerged globally as a dominant CA-MRSA lineage responsible for severe skin and soft tissue infections. In Japan, PVL-positive USA300-related clones have been increasingly identified in recent years, indicating ongoing diversification of community-associated MRSA lineages. This case illustrates the growing presence of USA300-related clones in Japan and the need for genomic surveillance and early intervention to prevent further spread in community settings.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder affecting the palms and soles. In rare cases, severe patients develop acute extra-palmoplantar lesions often accompanied by arthralgia. Such cases with extensive symptoms often necessitate systemic treatments with variable efficacy and potential side effects. Apremilast, known for its broad immune response modulation, presents promise as a therapeutic option for severe PPP with joint and extra-palmoplantar lesions. This case highlights apremilast as a potential systemic treatment for such cases with minimal side effects.

The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.

The skin is a pivotal barrier between the human body and the environment, and is a habitat for numerous microorganisms. While host–microbiota interactions in the skin are essential for homeostasis, disturbances in microbial composition and the abnormal growth of certain bacteria are associated with various diseases. Here, we identify strains and communities of skin commensals that contribute to or impair skin barrier function. Furthermore, we discuss the skin microenvironments suitable for specific microbiota that exert therapeutic effects and suggest focus areas for the prospective development of therapeutic strategies using bacterial agents. Finally, we highlight recent efforts to treat skin diseases associated with live bacteria.

Dominant-negative mutations associated with signal transducer and activator of transcription 3 (STAT3) signaling, which controls epithelial proliferation in various tissues, lead to atopic dermatitis in hyper IgE syndrome. This dermatitis is thought to be attributed to defects in STAT3 signaling in type 17 helper T cell　specification. However, the role of STAT3 signaling in skin epithelial cells remains unclear. We found that STAT3 signaling in keratinocytes is required to maintain skin homeostasis by negatively controlling the expression of hair follicle-specific keratin genes. These expression patterns correlated with the onset of dermatitis, which was observed in specific pathogen-free conditions but not in germ-free conditions, suggesting the involvement of Toll-like receptor-mediated inflammatory responses. Thus, our study suggests that STAT3-dependent gene expression in keratinocytes plays a critical role in maintaining the homeostasis of skin, which is constantly exposed to microorganisms.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS—genes in the mevalonate pathway—cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

TMEM79 is a predisposing gene for atopic dermatitis. Tmem79-deficient mice develop spontaneous dermatitis in a biphasic pattern. The first-phase dermatitis is unique because it occurs independent of microbiota status, whereas the second-phase dermatitis is microbiota dependent. In this study, we sought to identify the key factors mediating the development of first-phase dermatitis. Structural analysis showed that sebaceous gland hyperplasia started from first-phase dermatitis. Longitudinal RNA sequencing analysis revealed significant activation of fatty acid lipid metabolism pathways in first-phase dermatitis, whereas T helper 17‒based immune response genes were highly expressed in second-phase dermatitis. Quantitative RT-PCR analysis revealed that genes involved in fatty acid elongation and sebocyte differentiation were upregulated in first-phase dermatitis. The results of thin-layer chromatography supported these findings with an increased abundance of wax esters, cholesterol esters, and fatty alcohols in hair lipids. Further gas chromatography-tandem mass spectrometry analysis showed an increase in total fatty acid production, including that of elongated C20–24 saturated and C18–24 monounsaturated fatty acids. Collectively, these results suggest that aberrant production of sebaceous long-chain fatty acids is associated with microbiota-independent dermatitis. Further investigation of Tmem79-deficient mice may clarify the role of certain fatty acids in dermatitis.

The stratum corneum is the outermost skin layer with a vital role in skin barrier function. It is comprised of dead keratinocytes (corneocytes) and is known to maintain its thickness by shedding cells, although, the precise mechanisms that safeguard stratum corneum maturation and homeostasis remain unclear. Previous ex vivo studies have suggested a neutral-to-acidic pH gradient in the stratum corneum. Here, we use intravital pH imaging at single-corneocyte resolution to demonstrate that corneocytes actually undergo differentiation to develop three distinct zones in the stratum corneum, each with a distinct pH value. We identified a moderately acidic lower, an acidic middle, and a pH-neutral upper layer in the stratum corneum, with tight junctions playing a key role in their development. The upper pH neutral zone can adjust its pH according to the external environment and has a neutral pH under steady-state conditions owing to the influence of skin microbiota. The middle acidic pH zone provides a defensive barrier against pathogens. With mathematical modeling, we demonstrate the controlled protease activation of kallikrein-related peptidases on the stratum corneum surface that results in proper corneocyte shedding in desquamation. This work adds crucial information to our understanding of how stratum corneum homeostasis is maintained.