Skin metatranscriptomics reveals a landscape of variation in microbial activity and gene expression across the human body.

Metatranscriptomics methods for the skin are hampered by low microbial biomass, contamination with host cells and low RNA stability. In this study, we developed a robust, clinically tractable skin metatranscriptomics workflow that provides high technical reproducibility of profiles, uniform coverage across gene bodies and strong enrichment of microbial mRNAs. Paired application of this protocol with metagenomics to five skin sites in a cohort of 27 healthy adults identifies a notable divergence between transcriptomic and genomic abundances.

Microbial Makeover: Skin microbiome reset after stem cell transplantation.

Inborn errors of immunity disrupt host-microbe interactions. In this issue of Cell Host & Microbe, Che et al. examine DOCK8-deficient individuals undergoing stem cell transplantation and show that immune reconstitution rebalances the skin microbiome, underscoring the central role of immunity in shaping cutaneous microbial ecology.

Comparative analysis of 3D and 2D cell-culturing methods in hair follicle spheroid morphogenesis and drug responsiveness.

Three-dimensional (3D) cell-culturing methods have usually been considered superior to two-dimensional (2D) culturing for in-vitro tissue formation intended for tissue engineering and drug research applications, including hair follicle (HF) development. However, cellular interactions within 3D cultures are generally more complex and therefore, may require further investigation. Apart from grafting in-vitro cultured (2D and 3D) dermal papilla cells directly onto the skin of animals to study the impact of 3D culturing on hair inductivity, molecular studies remain lacking in the understanding of how 2D and 3D culturing methods influence the morphogenesis of early stage HF models.

Ruxolitinib Alleviates Inflammation and Fortifies Skin Barrier Function Through Dampening IL-13.

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder characterized by an impaired skin barrier, dysregulated immune system and pruritis. Emerging pharmaceutical therapies for AD include selective Janus kinase (JAK) inhibitors such as ruxolitinib, the first dual JAK1/JAK2 inhibitor approved by the US Food and Drug Administration. This study aimed to evaluate the effects of ruxolitinib on AD-related symptoms using mouse and human skin models.

Protocol to reconstruct an in vitro 3D full-thickness skin equivalent model with collagen I in 6- and 12-well inserts.

In vitro 3D full-thickness reconstituted human skin has high physiological relevance due to the presence of differentiation features often lacking in 2D cell cultures. Here, we present a protocol to reconstruct a 3D skin model using human fibroblasts, keratinocytes, and rat-tail collagen I. We describe steps for cell expansion, the casting of cellular and acellular layers, seeding keratinocytes, the air lifting of culture, and incubation.

Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation.

In 2020-2021, a "mysterious illness" struck Senegalese fishermen, causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity. Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins. Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes, which subsequently activates the stress kinases ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/IL-18 pro-inflammatory cytokines and cell death.

Highly accurate, noninvasive early identification of infants with a filaggrin loss-of-function mutation by in vivo Raman spectroscopy, followed from birth to 12 months.

Background: Loss-of-function FLG mutation (FLGmut) carriers are at an increased risk of developing atopic dermatitis (AD), characterized by earlier onset and more severe disease. AD is driven by a complex interplay between skin barrier function, T2 and T2-dominant immune dysregulation, and dysbiosis. Results from the Short-Term Topical Application for Prevention of Atopic Dermatitis study suggest 2 early initiating AD pathogenetic pathways: an FLGmut-related skin barrier deficiency pathway and an immune function-related inflammatory pathway.

The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo.

Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation.

The skin microbiome in pediatric atopic dermatitis and food allergy.

The skin microbiome is an extensive community of bacteria, fungi, mites, viruses and archaea colonizing the skin. Fluctuations in the composition of the skin microbiome have been observed in atopic dermatitis (AD) and food allergy (FA), particularly in early life, established disease, and associated with therapeutics. However, AD is a multifactorial disease characterized by skin barrier aberrations modulated by genetics, immunology, and environmental influences, thus the skin microbiome is not the sole feature of this disease.

A Malassezia pseudoprotease dominates the secreted hydrolase landscape and is a potential allergen on skin.

Malassezia globosa is abundant and prevalent on sebaceous areas of the human skin. Genome annotation reveals that M. globosa possesses a repertoire of secreted hydrolytic enzymes relevant for lipid and protein metabolism.

Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis.

The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors.

Early initiation of short-term emollient use for the prevention of atopic dermatitis in high-risk infants-The STOP-AD randomised controlled trial.

Background: Protecting the skin barrier in early infancy may prevent atopic dermatitis (AD). We investigated if daily emollient use from birth to 2 months reduced AD incidence in high-risk infants at 12 months.

Methods: This was a single-center, two-armed, investigator-blinded, randomized controlled clinical trial (NCT03871998).

Expression of Virulence Factors in Atopic Dermatitis.

Atopic dermatitis (AD) is a skin inflammatory disease in which the opportunistic pathogen is prevalent and abundant. harbors several secreted virulence factors that have well-studied functions in infection models, but it is unclear whether these extracellular microbial factors are relevant in the context of AD. To address this question, we designed a culture-independent method to detect and quantify virulence factors expressed at the skin sites.

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome.

Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1) by MAP3K20/ZAKα kinase and its downstream effector, p38.

Distinct skin microbiome community structures in congenital ichthyosis.

Background: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored.

Objectives: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes.

Shared signatures and divergence in skin microbiomes of children with atopic dermatitis and their caregivers.

Background: Atopic dermatitis (AD) is a common chronic skin condition in children (15-20%) that can significantly impair their quality of life. As a result of its relapsing nature and enrichment of Staphylococcus aureus during flares, clinical management can include eradicating S aureus from the skin of children; however, this does not extend to their healthy caregivers, who are potential reservoirs.

Objective: Our aim was to understand skin microbiome sharing and microbial features in children with AD and their healthy adult caregivers.