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Background: Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood., Objective: We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity., Methods: We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures., Results: S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C 18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C 16:0 →C 18:0 ) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21., Conclusion: CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6., Competing Interests: Disclosure statement Supported by grants from the National Institutes of Health (NIH), including T32GM007356 (to H.M.K.), F30AG076326 (H.M.K.), U19AI117673 (Atopic Dermatitis Research Network [ADRN] investigators), UM1AI151958 (ADRN investigators), UM2AI117870 (Rho Inc), and UM1TR004399 (University of Colorado investigators). This article’s contents are the authors’ sole responsibility and do not necessarily represent official NIH views. Disclosure of potential conflict of interest: L. A. Beck has been consultant for Allakos, Arcutis Biotherapeutics, Arena Pharmaceuticals, Dermavent, DermTech, Evelo Biosciences, Galderma, Incyte, Janssen, LEO Pharma, Merck, Nektar Therapeutics, Numab Therapeutics, Pfizer, Rapt Therapeutics, Regeneron, Ribon Therapeutics, Sanofi/Genzyme, Sanofi-Aventis, Stealth BioTherapeutics, Trevi Therapeutics, Union Therapeutics, and Xencor; and investigator for AbbVie, AstraZeneca, DermTech, Kiniksa, Pfizer, Regeneron, Ribon Therapeutics, and Sanofi. M. Boguniewicz has been investigator and advisory board member for Regeneron and Sanofi. Z. C. Chiesa Fuxench has received research grants from Lilly, Brexogen, LEO Pharma, Regeneron, Sanofi, Tioga, and Vanda for work related to atopic dermatitis, and from Menlo Therapeutics and Galderma for work related to prurigo nodularis; has served as consultant for the Asthma and Allergy Foundation of America, National Eczema Association, AbbVie, Incyte, and Pfizer; and received honoraria for continuing medical education work in atopic dermatitis sponsored by education grants from Regeneron/Sanofi and Pfizer and from Beirsdorf for work related to skin cancer and sun protection. A. De Benedetto has been a consultant for AbbVie, Incyte, and Sanofi-Advent; and has received grant or clinical trial support paid to institution from Incyte and Pfizer. D. Y. M. Leung reports grants to his institution from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Genentech, and Sanofi; and personal consulting fees from Sanofi, Jasper Therapeutics, and Leo Pharma. P. Y. Ong has been on advisory boards for Dermavant, Amgen, Johnson & Johnson, and AbbVie; and has received research funding from Incyte, Leo, Regeneron, and Sanofi. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Lipids are important skin components that provide, together with proteins, barrier function of the skin. Keratinocyte terminal differentiation launches unique metabolic changes to lipid metabolism that result in the predominance of ceramides within lipids of the stratum corneum (SC)-the very top portion of the skin. Differentiating keratinocytes form unique ceramides that can be found only in the skin, and generate specialized extracellular structures known as lamellae. Lamellae establish tight hydrophobic layers between dying keratinocytes to protect the body from water loss and also from penetration of allergens and bacteria. Genetic and immunological factors may lead to the failure of keratinocyte terminal differentiation and significantly alter the proportion between SC components. The consequence of such changes is loss or deterioration of skin barrier function that can lead to pathological changes in the skin. This review summarizes our current understanding of the role of lipids in skin barrier function. It also draws attention to the utility of testing SC for lipid and protein biomarkers to predict future onset of allergic skin diseases., Competing Interests: The author has research grants and contracts from Sanofi-Genzyme and from LEO Pharma., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Purpose: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood., Experimental Design: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays., Results: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo., Conclusions: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions., (©2024 The Authors; Published by the American Association for Cancer Research.)

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Karpurapu, Nie, Chung, Yan, Dougherty, Pannu, Wisler, Harkless, Parinandi, Berdyshev, Pei and Christman.)

Background: Food allergy (FA) often occurs in early childhood with and without atopic dermatitis (AD). FA can be severe and even fatal. For primary prevention, it is important to find early biomarkers to predict the future onset of FA before any clinical manifestations., Objective: Our aim was to find early predictors of future onset of FA in the stratum corneum (SC)., Methods: Skin tape strips were collected from the forearm of newborns (n = 129) at age 2 months, before any signs of clinical FA or AD. Children were clinically monitored until they reached age 2 years to confirm the presence or absence of FA and AD. Skin tape strips were subjected to lipidomic analyses by liquid chromatography-tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay., Results: Overall, 9 of 129 infants (7.0%) developed FA alone and 9 of 129 infants (7.0%) developed FA concomitantly with AD. In the stratum corneum of children with future FA and concomitant AD and FA, absolute amounts of unsaturated (N24:1)(C18-sphingosine)ceramide and (N26:1)(C18-sphingosine)ceramide and their relative percentages within the molecular group were increased compared with the amounts and percentages in healthy children, with P values ranging from less than .01 to less than .05 according to ANOVA. The children with future AD had normal levels of these molecules. IL-33 level was upregulated in those infants with future FA but not in those with future AD, whereas thymic stromal lymphopoietin was upregulated in those with future AD but not in those with future FA. Logistic regression analysis revealed strong FA predicting power for the combination of dysregulated lipids and cytokines, with an odds ratio reaching 101.4 (95% CI = 5.4-1910.6)., Conclusion: Noninvasive skin tape strip analysis at age 2 months can identify infants at risk of FA in the future., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)