特应性皮炎（AD）前沿文献精读特辑（Nature / J Invest Dermatol）

The establishment of the infant gut microbiome is critical for later health1,2, yet how it is shaped by maternal and early-life factors remains unclear. Here we metagenomically sequenced 4,526 longitudinal faecal samples from 714 mother-infant pairs in the Dutch birth cohort Lifelines NEXT, spanning 12 weeks of pregnancy to 1 year postpartum. We integrated these data with 474 clinical and exposure variables, and with ultra-deep sequencing of breast milk and vaginal microbiomes. We observe that the maternal gut microbiome undergoes only subtle changes during pregnancy and postpartum, influenced by diet, infections and pre-pregnancy smoking. The maternal gut microbiome is a major reservoir for infant gut strains, with only occasional transmission from vaginal and breast milk microbiomes. Mother-infant gut strain sharing is time dependent, and higher maternal gut species abundance increases the likelihood of strain transmission. We find that the maternal gut microbiome is a predictor of infant eczema. Mode of delivery and feeding mode primarily shaped the infant gut microbiome and its functional profiles, with maternal exposures also having a role. Of 585 vaginally delivered infants, 155 were born at home, but home delivery was only moderately associated with infant gut microbiome composition, similar to other birth parameters such as duration of pushing and ruptured membranes. Overall, we highlight the central role of the mother and her microbiome in shaping the infant gut ecosystem and early health outcomes.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by an aberrant T helper 2 immune response and impaired epidermal barrier function, regardless of phenotypes and endotypes. Historically, AD has been extensively studied in mouse models, which have intrinsic limitations, notably in the translatability of results to patients. Moreover, ethical concerns have driven the field toward the development of organotypic AD skin models. The recent steep increase in their use warrants an expert opinion on the advantages and limitations of such models and opportunities for their improvement, which are presented in this paper.

The Mas-related G-protein-coupled receptor X2 is a promiscuous receptor expressed on mast cells that mediates IgE-independent mast cell activation and degranulation in response to a variety of diverse agonists and has been implicated in numerous inflammatory conditions, including atopic dermatitis (AD). We investigated whether the small-molecule Mas-related G-protein-coupled receptor X2 antagonist INCB000262 improves disease phenotype in the house dust mite + Staphylococcus aureus enterotoxin type B (HDM+SEB) mouse model of AD and further characterized mast cell-mediated aspects of disease. Mas-related G-protein-coupled receptor X2 knock-in mice were sensitized to HDM+SEB and orally dosed once daily with either vehicle or INCB000262 for 4 weeks, and efficacy and skin transcriptional changes were evaluated. INCB000262 attenuated HDM+SEB-induced AD in vivo, with improvements observed in skin thickness, transepidermal water loss, tissue weight, and overall clinical score. In addition, transcriptome changes induced by HDM+SEB exhibited a mast cell activation signature consistent with human AD lesional skin, which was attenuated by antagonist treatment. Overall, INCB000262, a Mas-related G-protein-coupled receptor X2 antagonist, attenuated HDM+SEB-induced AD disease phenotypes and mast cell-associated transcriptional changes, supporting further evaluation of INCB000262 as an oral treatment for AD and other mast cell-mediated diseases.

Itch is the cardinal symptom contributing to patient burden in atopic dermatitis. Multiple validated itch scales are used in clinical trials, generating heterogeneous datasets. In addition, recent studies suggest an association between cytokine levels and disease severity in atopic dermatitis. This study aimed to compare the performance of different validated itch instruments and their relationship to blood cytokine profiles. Forty-nine adults with severe atopic dermatitis and severe itch were treated with 300 mg dupilumab for 16 weeks. At the initial assessment and after treatment, itch intensity and QOL were evaluated using various assessment tools. Peripheral blood samples were collected at both time points for cytokine profiling. All itch intensity scales demonstrated comparable responsiveness, irrespective of their dimension; however, the numerical rating scale consistently yielded higher scores than the visual analog scale. Macrophage-derived chemokine, CCL26, B-cell-activating factor, and IL-2R levels were significantly reduced after treatment and correlated with all (macrophage-derived chemokine and B-cell-activating factor) or subsets (CCL26 and IL-2R) of itch intensity and QOL scores. In conclusion, all validated itch intensity scales are suitable for routine clinical use; however, adhering to one instrument is recommended. The observed correlations between cytokine levels and itch scales suggest their potential as markers of disease burden in atopic dermatitis.

IGF-Like (IGFL) Family member proteins are a putative cytokine family whose functions are not defined. Here we demonstrate that IGFL1 and IGFL4 are significantly increased in lesional atopic dermatitis (AD) skin and mouse Igfl is significantly increased in an oxazolone (Oxa)-induced model of allergic skin inflammation. In addition, studies with Igfl-deficient mice revealed significant reductions in markers of disease severity. RNA sequencing and qPCR demonstrated reduced Il4, Il13, and other type 2 inflammation-associated transcripts in Oxa treated skin from Igfl-deficient mice. As the Oxa model is Th2 cytokine-dependent, we hypothesized IL-4 and/or IL-13 promote Igfl expression. In support of this, we discovered Il4 precedes Igfl induction in the Oxa model. We then identified mouse keratinocytes as a source of Igfl and found stimulation with IL-4 or IL-13 promoted Igfl expression in these cells, while IFNγ did not. Stimulation of human keratinocytes with IL-4 or IL-13 induced IGFL4. In vivo experiments also demonstrated that Igfl induction is dependent on IL-4Rα in the Oxa model, and AD patients who received dupilumab or tralokinumab treatment showed decreased IGFL4 expression in lesional skin. These data suggest there is a positive feedback loop between IL-4/IL-13 and IGFLs that can promote allergic skin inflammation.