{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:21:38Z","timestamp":1787509298690,"version":"build-2736575974"},"reference-count":87,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["P01 AI106684"],"award-info":[{"award-number":["P01 AI106684"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R35 HL166219"],"award-info":[{"award-number":["R35 HL166219"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01 AI176632"],"award-info":[{"award-number":["R01 AI176632"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["K08 HL164887"],"award-info":[{"award-number":["K08 HL164887"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01 HL153058"],"award-info":[{"award-number":["R01 HL153058"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["DP2AI164325"],"award-info":[{"award-number":["DP2AI164325"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"<jats:p>\n                    Type 2 (T2) immune cells dominate the airways of patients with mild-moderate asthma (MMA) with a more complex type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of patients with SA and MMA would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered, and IFN-inducible mucins,\n                    <jats:italic>MUC1<\/jats:italic>\n                    and\n                    <jats:italic>MUC4<\/jats:italic>\n                    , was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in 2 separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared with MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.202442","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:00:20Z","timestamp":1785427220000},"source":"Crossref","is-referenced-by-count":0,"title":["Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning"],"prefix":"10.1172","volume":"11","author":[{"given":"Sagar L.","family":"Kale","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusta","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6009-0787","authenticated-orcid":true,"given":"Isha","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Calderon","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Ramonell","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu","family":"Setya","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica C.","family":"McCreary-Partyka","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1550-2815","authenticated-orcid":true,"given":"Stephanie A.","family":"Christenson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-0603","authenticated-orcid":true,"given":"Prescott G.","family":"Woodruff","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Castro","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaharu","family":"Sumino","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar N.","family":"Jarjour","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren C.","family":"Denlinger","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Gaston","sequence":"additional","affiliation":[{"name":"Riley Hospital for Children and Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene R.","family":"Bleecker","sequence":"additional","affiliation":[{"name":"Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy C.","family":"Moore","sequence":"additional","affiliation":[{"name":"Section on Pulmonary, Critical Care, Allergy & Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliot","family":"Israel","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-5731","authenticated-orcid":true,"given":"Bruce D.","family":"Levy","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Mauger","sequence":"additional","affiliation":[{"name":"Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, University Park, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serpil","family":"Erzurum","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Newbrough","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor J.","family":"Nee","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabir","family":"Ray","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"},{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudette M.","family":"St. Croix","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7761-9109","authenticated-orcid":true,"given":"Sally E.","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"},{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Department of Environmental and Occupational Health, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5747-064X","authenticated-orcid":true,"given":"Jishnu","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Ray","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"},{"name":"Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5037-2804","authenticated-orcid":true,"given":"Marc C.","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2678"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2019"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.08.042"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00202013"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.11.037"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ado6649"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adu4913"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.018"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6130"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/imr.70011"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2023.09.003"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108974"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80911"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/thorax-2022-219781"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02420-2019"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-070323-103158"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.05.031"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.000333"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI5155"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.1993.tb00367.x"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.152.5.2546"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200310-1416OC"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43598"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.94580"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.05.044"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.02.028"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201607-1407OC"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.816"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02135-2016"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202102-0355OC"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.08.020"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202402-0403OC"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02175-z"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01986-8"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk7832"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.180239"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq9133"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.149945"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.185758"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0149-2020"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.70.113006.100659"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0910061"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.122475"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2022.120942"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202407-1504OC"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-008-0098-3"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.74"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.6.9712073"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201512-2452OC"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2017-0162OC"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2222.2002.01477.x"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018075108"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.044"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02525-x"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.06.011"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.108805"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1995.tb02696.x"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.05.015"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3390\/cells8080807"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2025.114169"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2008-0169TR"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.01.001"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.16"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02374-20"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22106"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90970-7"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0100645"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/path.4375"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302630200"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009449200"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02222-06"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210532"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-14-85"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-7-39"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.185061"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-9673rev"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1130-8"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0347-8"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07377-1"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.04.015"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph17176212"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2024.12.015"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-025-02723-1"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1411863"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.12.1084"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1039\/C5MB00663E"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/202442\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:01:30Z","timestamp":1787508090000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/202442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":87,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,7,16]]},"published-print":{"date-parts":[[2026,8,24]]}},"alternative-id":["10.1172\/jci.insight.202442"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.202442","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"article-number":"e202442"}}