{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T17:58:34Z","timestamp":1788026314737,"version":"build-2784847793"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      is the leading cause of bacterial skin infections in several inflammatory skin diseases, however, is rarely detected on healthy skin. Skin barrier defects, such as in atopic dermatitis, promote\n                      <jats:italic>S. aureus<\/jats:italic>\n                      colonization by yet unknown mechanism. In our previous work we found that in healthy skin commensal staphylococci including Staphylococcus epidermidis and Staphylococcus lugdunensis (SL) protect against\n                      <jats:italic>S. aureus<\/jats:italic>\n                      skin colonization, however, the microbiome-mediated protection is lost in inflammatory skin. Here, we investigated how microbiome-derived factors contribute to skin defense under homeostatic and inflammatory conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We examined how bacterial conditioned media (BCM) from\n                      <jats:italic>S. epidermidis<\/jats:italic>\n                      and\n                      <jats:italic>S. lugdunensis<\/jats:italic>\n                      influence immune responses in primary human keratinocytes, human skin explants, and 3D skin reconstructs. Immune signaling was assessed using LEGENDplex cytokine profiling, RT2 Profiler PCR arrays, and western blotting. To investigate how BCM pretreatment limits\n                      <jats:italic>S. aureus<\/jats:italic>\n                      colonization, we performed inhibitor studies with a focus on aryl hydrocarbon receptor (AHR) signaling. The effects of BCM under inflammatory conditions were analyzed in tape-stripped human skin explants and 3D skin models with an atopic dermatitis\u2013like phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that released factors from SE and SL reduce\n                      <jats:italic>S. aureus<\/jats:italic>\n                      skin colonization by inducing antimicrobial peptides (AMPs) and suppressing inflammatory responses in the skin. Both, factors released by SE and SL, limit\n                      <jats:italic>S. aureus<\/jats:italic>\n                      -induced immune activation in the skin by dampening inflammatory signaling, reducing reactive oxygen species, and suppressing expression of danger-associated molecular patterns (DAMPs). We show that this anti-inflammatory effect is mediated by activation of aryl hydrocarbon receptor (AHR) signaling in keratinocytes. Mechanistically, SE and SL membrane vesicles are involved in activating AHR signaling in keratinocytes via direct vesicle-cell contact as well as by bacterial tryptophan metabolites. This protective effect is lost in inflamed skin, where it instead exacerbated inflammation due to impaired AHR activity in inflamed skin. Interestingly, co-treatment of human AD-like skin equivalents with released SE factors together with an AHR ligand effectively reduces\n                      <jats:italic>S. aureus<\/jats:italic>\n                      colonization pointing out a potential novel AHR- and microbiome-based therapeutic strategy in AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Together, these findings highlight a context-dependent role of microbiome-derived factors in shaping cutaneous immunity and underscore the therapeutic potential of restoring AHR signaling to enhance the skin\u2019s defense against\n                      <jats:italic>S. aureus<\/jats:italic>\n                      , particularly in inflammatory disorders such as AD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1726557","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:51:46Z","timestamp":1764600706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Commensal Staphylococci attenuate Staphylococcus aureus skin colonization and inflammation via AHR-dependent signaling"],"prefix":"10.3389","volume":"16","author":[{"given":"Jule","family":"Riebelmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Kienzle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Sauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Schittek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(05)70295-4","article-title":"The role of nasal carriage in Staphylococcus aureus infections","volume":"5","author":"Wertheim","year":"2005","journal-title":"Lancet Infect Dis"},{"key":"B2","article-title":"Coagulase positive staphylococcal colonization of humans and their household pets","volume":"50","author":"Hanselman","year":"2009","journal-title":"Can Vet J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2009.09229.x","article-title":"Isolation of alpha-toxin-producing Staphylococcus aureus from the skin of highly sensitized adult patients with severe atopic dermatitis","volume":"161","author":"Wichmann","year":"2009","journal-title":"Br J Dermatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.03.014","article-title":"Dysbiosis and staphylococcus aureus colonization drives inflammation in atopic dermatitis","volume":"42","author":"Kobayashi","year":"2015","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2309243121","article-title":"Staphylococcus aureus proteases trigger eosinophil-mediated skin inflammation","volume":"121","author":"Kline","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/all.15640","article-title":"Staphylococcus aureus causes aberrant epidermal lipid composition and skin barrier dysfunction","volume":"78","author":"Kim","year":"2023","journal-title":"Allergy"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5375","DOI":"10.1016\/j.cell.2023.10.019","article-title":"S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis","volume":"186","author":"Deng","year":"2023","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"464","DOI":"10.3390\/toxins14070464","article-title":"Exploring the role of staphylococcus aureus in inflammatory diseases","volume":"14","author":"Chen","year":"2022","journal-title":"Toxins (Basel)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2021.1975909","article-title":"Phenol-soluble modulins alpha are major virulence factors of Staphylococcus aureus secretome promoting inflammatory response in human epidermis","volume":"12","author":"Damour","year":"2021","journal-title":"Virulence"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1101\/gr.131029.111","article-title":"Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis","volume":"22","author":"Kong","year":"2012","journal-title":"Genome Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.05.026","article-title":"Rapid reduction in Staphylococcus aureus in atopic dermatitis subjects following dupilumab treatment","volume":"152","author":"Simpson","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260144","article-title":"Dialogue between skin microbiota and immunity","volume":"346","author":"Belkaid","year":"2014","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.tim.2019.01.008","article-title":"Commensal staphylococci influence staphylococcus aureus skin colonization and disease","volume":"27","author":"Parlet","year":"2019","journal-title":"Trends Microbiol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1038\/s41467-019-10646-7","article-title":"Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors","volume":"10","author":"Bitschar","year":"2019","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01256-2","article-title":"Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial","volume":"27","author":"Nakatsuji","year":"2021","journal-title":"Nat Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2010.328","article-title":"Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways","volume":"131","author":"Wanke","year":"2011","journal-title":"J Invest Dermatol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14478","article-title":"Bacterial membrane vesicles shape Staphylococcus aureus skin colonization and induction of innate immune responses","volume":"31","author":"Staudenmaier","year":"2022","journal-title":"Exp Dermatol"},{"key":"B18","doi-asserted-by":"crossref","DOI":"10.1038\/nature19781","article-title":"Human commensals producing a novel antibiotic impair pathogen colonization (vol 535, 511, 2016)","volume":"539","author":"Zipperer","year":"2016","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2024.01.006","article-title":"A Staphylococcus epidermidis strain inhibits the uptake of Staphylococcus aureus derived from atopic dermatitis skin into the keratinocytes","volume":"113","author":"Numata","year":"2024","journal-title":"J Dermatol Sci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1016\/j.chom.2021.05.011","article-title":"Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor","volume":"29","author":"Uberoi","year":"2021","journal-title":"Cell Host Microbe"},{"key":"B21","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.chom.2019.10.007","article-title":"Toxin-triggered interleukin-1 receptor signaling enables early-life discrimination of pathogenic versus commensal skin bacteria","volume":"26","author":"Leech","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B22","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s40168-018-0404-9","article-title":"Commensal microbiota modulate gene expression in the skin","volume":"6","author":"Meisel","year":"2018","journal-title":"Microbiome"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg6262","article-title":"Commensal Cutibacterium acnes induce epidermal lipid synthesis important for skin barrier function","volume":"9","author":"Almoughrabie","year":"2023","journal-title":"Sci Adv"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14727","article-title":"The influence of the commensal skin bacterium Staphylococcus epidermidis on the epidermal barrier and inflammation: Implications for atopic dermatitis","volume":"32","author":"Ochlich","year":"2023","journal-title":"Exp Dermatol"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.1159\/000492162","article-title":"Staphylococcus epidermidis activates aryl hydrocarbon receptor signaling in human keratinocytes: implications for cutaneous defense","volume":"11","author":"Rademacher","year":"2019","journal-title":"J Innate Immun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212397","article-title":"A dysregulated sebum-microbial metabolite-IL-33 axis initiates skin inflammation in atopic dermatitis","volume":"219","author":"Qiu","year":"2022","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.chembiol.2024.12.007","article-title":"Commensal-derived tryptophan metabolites fortify the skin barrier: Insights from a 50-species gnotobiotic model of human skin microbiome","volume":"32","author":"Uberoi","year":"2025","journal-title":"Cell Chem Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5951","DOI":"10.3390\/molecules29245951","article-title":"Natural products as modulators of aryl hydrocarbon receptor signaling in atopic dermatitis management","volume":"29","author":"Lee","year":"2024","journal-title":"Molecules"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1323405","DOI":"10.3389\/falgy.2024.1323405","article-title":"Aryl hydrocarbon receptor and IL-13 signaling crosstalk in human keratinocytes and atopic dermatitis","volume":"5","author":"Proper","year":"2024","journal-title":"Front Allergy"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2023.02.005","article-title":"Targeting skin barrier function in atopic dermatitis","volume":"11","author":"van den Bogaard","year":"2023","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.3390\/ijms23031773","article-title":"Carboxamide derivatives are potential therapeutic AHR ligands for restoring IL-4 mediated repression of epidermal differentiation proteins","volume":"23","author":"Rikken","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01264-z","article-title":"The AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes epidermal and immune homeostasis in atopic dermatitis-like skin inflammation","volume":"22","author":"Chen","year":"2025","journal-title":"Cell Mol Immunol"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1016\/j.jid.2016.11.024","article-title":"The protective effect of microbiota on S. aureus skin colonization depends on the integrity of the epithelial barrier","volume":"137","author":"Burian","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1098160","DOI":"10.3389\/fimmu.2023.1098160","article-title":"Staphylococcus epidermidis isolates from atopic or healthy skin have opposite effect on skin cells: potential implication of the AHR pathway modulation","volume":"14","author":"Landemaine","year":"2023","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"113024","DOI":"10.1016\/j.celrep.2023.113024","article-title":"Staphylococcus epidermidis activates keratinocyte cytokine expression and promotes skin inflammation through the production of phenol-soluble modulins","volume":"42","author":"Williams","year":"2023","journal-title":"Cell Rep"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1352704","DOI":"10.3389\/fimmu.2024.1352704","article-title":"The extracellular serine protease from Staphylococcus epidermidis elicits a type 2-biased immune response in atopic dermatitis patients","volume":"15","author":"Abdurrahman","year":"2024","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.jaci.2020.06.024","article-title":"Staphylococcus epidermidis protease EcpA can be a deleterious component of the skin microbiome in atopic dermatitis","volume":"147","author":"Cau","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.050541","article-title":"Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis","volume":"17","author":"Scheurer","year":"2024","journal-title":"Dis Model Mech"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14478","article-title":"Bacterial membrane vesicles shape skin colonization and induction of innate immune responses","volume":"31","author":"Staudenmaier","year":"2022","journal-title":"Exp Dermatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01851-18","article-title":"The Mechanism behind Bacterial Lipoprotein Release: Phenol-Soluble Modulins Mediate Toll-Like Receptor 2 Activation via Extracellular Vesicle Release from Staphylococcus aureus","volume":"9","author":"Schlatterer","year":"2018","journal-title":"mBio"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14409","article-title":"The aryl hydrocarbon receptor at the forefront of host-microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications","volume":"30","author":"van den Bogaard","year":"2021","journal-title":"Exp Dermatol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/jambio\/lxae273","article-title":"Activation of the aryl hydrocarbon receptor via indole derivatives is a common feature in skin bacterial isolates","volume":"135","author":"Elias","year":"2024","journal-title":"J Appl Microbiol"},{"key":"B43","article-title":"Treatment of staphylococcus aureus infections","volume":"409","author":"David","year":"2017","journal-title":"Curr Top Microbiol Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2010.123","article-title":"Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections","volume":"130","author":"Lai","year":"2010","journal-title":"J Invest Dermatol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"9551","DOI":"10.3390\/ijms23179551","article-title":"Potential Therapeutic Skin Microbiomes Suppressing Staphylococcus aureus-Derived Immune Responses and Upregulating Skin Barrier Function-Related Genes via the AhR Signaling Pathway","volume":"23","author":"Lee","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1016\/j.jid.2024.03.033","article-title":"Commensal skin bacteria exacerbate inflammation and delay skin barrier repair","volume":"144","author":"Khadka","year":"2024","journal-title":"J Invest Dermatol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307321110","article-title":"Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice","volume":"110","author":"Imai","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B48","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12950-025-00438-w","article-title":"Biological mechanisms and therapeutic prospects of interleukin-33 in pathogenesis and treatment of allergic disease","volume":"22","author":"Jamali","year":"2025","journal-title":"J Inflammation (Lond)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1016\/j.jid.2021.04.002","article-title":"Nuclear IL-33 plays an important role in the suppression of FLG, LOR, keratin 1, and keratin 10 by IL-4 and IL-13 in human keratinocytes","volume":"141","author":"Dai","year":"2021","journal-title":"J Invest Dermatol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1016\/j.jaci.2015.01.048","article-title":"IL-33 impacts on the skin barrier by downregulating the expression of filaggrin","volume":"135","author":"Seltmann","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-2552","article-title":"The \"Alarmins\" HMBG1 and IL-33 downregulate structural skin barrier proteins and impair epidermal growth","volume":"97","author":"Nygaard","year":"2017","journal-title":"Acta Derm Venereol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax2945","article-title":"Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis","volume":"11","author":"Chen","year":"2019","journal-title":"Sci Transl Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.jid.2019.10.017","article-title":"Staphylococcus aureus skin colonization is enhanced by the interaction of neutrophil extracellular traps with keratinocytes","volume":"140","author":"Bitschar","year":"2020","journal-title":"J Invest Dermatol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/all.16644","article-title":"Phytic acid improves the skin barrier function in murine models of atopic dermatitis through skin microbiota-derived indole-3-propionic acid","volume":"80","author":"Wang","year":"2025","journal-title":"Allergy"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1016\/j.jaci.2018.11.036","article-title":"A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor","volume":"143","author":"Yu","year":"2019","journal-title":"J Allergy Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1726557\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:51:48Z","timestamp":1764600708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1726557\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2025.1726557"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1726557","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"article-number":"1726557"}}