{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T22:53:31Z","timestamp":1771541611002,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T00:00:00Z","timestamp":1658793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["DR1013\/1-1"],"award-info":[{"award-number":["DR1013\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["BMBF16LW0140"],"award-info":[{"award-number":["BMBF16LW0140"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Ministry of Education and Research","doi-asserted-by":"publisher","award":["DR1013\/1-1"],"award-info":[{"award-number":["DR1013\/1-1"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Ministry of Education and Research","doi-asserted-by":"publisher","award":["BMBF16LW0140"],"award-info":[{"award-number":["BMBF16LW0140"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Saarland University","award":["DR1013\/1-1"],"award-info":[{"award-number":["DR1013\/1-1"]}]},{"name":"Saarland University","award":["BMBF16LW0140"],"award-info":[{"award-number":["BMBF16LW0140"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Severe epithelial dysfunction is one major hallmark throughout the pathophysiological progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1), cytokines (e.g., TNF\u03b1), and growth factors (e.g., TGF\u03b1), controlling proper lung barrier function and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung epithelial cells with Pseudomonas aeruginosa and Exotoxin A (ExoA), without any impact of infection by Streptococcus pneumoniae. The characterization of released extracellular vesicles\/exosomes and the comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that its activation during infection with Pseudomonas aeruginosa was critical for the cleavage of junctional adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option in Pseudomonas aeruginosa lung infection preventing severe epithelial and organ dysfunctions and stimulating future translational studies.<\/jats:p>","DOI":"10.3390\/cells11152303","type":"journal-article","created":{"date-parts":[[2022,7,26]],"date-time":"2022-07-26T22:03:42Z","timestamp":1658873022000},"page":"2303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pseudomonas aeruginosa Alters Critical Lung Epithelial Cell Functions through Activation of ADAM17"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0982-3583","authenticated-orcid":false,"given":"Ahmad","family":"Aljohmani","sequence":"first","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah Niklas","family":"Andres","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Yildiz","sequence":"additional","affiliation":[{"name":"Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1086\/506430","article-title":"Acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data","volume":"43","author":"Bauer","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1056\/NEJMra0904124","article-title":"Hospital-Acquired Infections Due to Gram-Negative Bacteria","volume":"362","author":"Peleg","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"538","DOI":"10.7861\/clinmedicine.12-6-538","article-title":"Community-acquired pneumonia","volume":"12","author":"Brown","year":"2012","journal-title":"Clin. Med. (Lond.)"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/2049-632X.12033","article-title":"Pseudomonas aeruginosa: New insights into pathogenesis and host defenses","volume":"67","author":"Gellatly","year":"2013","journal-title":"Pathog. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1056\/NEJMra022387","article-title":"Hydrophobic Surfactant Proteins in Lung Function and Disease","volume":"347","author":"Whitsett","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/nri2236","article-title":"Regulation of immunological homeostasis in the respiratory tract","volume":"8","author":"Holt","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1165\/rcmb.2011-0011RT","article-title":"Innate Immunity in the Respiratory Epithelium","volume":"45","author":"Parker","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.tim.2005.05.011","article-title":"Modulation of lung epithelial functions by Pseudomonas aeruginosa","volume":"13","author":"Lau","year":"2005","journal-title":"Trends Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fmicb.2011.00155","article-title":"Protein Secretion Systems in Pseudomonas aeruginosa: An Essay on Diversity, Evolution, and Function","volume":"2","author":"Filloux","year":"2011","journal-title":"Front. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wagener, B.M., Hu, R., Wu, S., Pittet, J.-F., Ding, Q., and Che, P. (2021). The Role of Pseudomonas aeruginosa Virulence Factors in Cytoskeletal Dysregulation and Lung Barrier Dysfunction. Toxins, 13.","DOI":"10.3390\/toxins13110776"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1099\/00222615-43-3-169","article-title":"Role of exotoxin A in inducing severe Pseudomonas aeruginosa infections in mice","volume":"43","author":"Miyazaki","year":"1995","journal-title":"J. Med. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Aljohmani, A., Opitz, B., Bischoff, M., and Yildiz, D. (2022). Pseudomonas aeruginosa Triggered Exosomal Release of ADAM10 Mediates Proteolytic Cleavage in Trans. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031259"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1165\/ajrcmb.15.1.8679217","article-title":"Pseudomonas aeruginosa and epithelial permeability: Role of virulence factors elastase and exotoxin A","volume":"15","author":"Azghani","year":"1996","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ejcb.2011.09.003","article-title":"The role of ADAM-mediated shedding in vascular biology","volume":"91","author":"Dreymueller","year":"2012","journal-title":"Eur. J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"608281","DOI":"10.3389\/fcvm.2020.608281","article-title":"A Disintegrin and Metalloproteinase\u2014Control Elements in Infectious Diseases","volume":"7","author":"Aljohmani","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1080\/003655401750173968","article-title":"Circulating soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in immunocompetent and renal transplant patients: Correlation with cytomegalovirus disease and renal function","volume":"33","author":"Eriksson","year":"2001","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/emmm.201200217","article-title":"Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide","volume":"4","author":"Dreymueller","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Seifert, A., Wozniak, J., Dusterhoft, S., Kasparek, P., Sedlacek, R., Dreschers, S., Orlikowsky, T.W., Yildiz, D., and Ludwig, A. (2020). The iRhom2\/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21175978"},{"key":"ref_19","first-page":"91","article-title":"Studying the effects of several heat-inactivated bacteria on colon and breast cancer cells","volume":"8","author":"Rabiei","year":"2019","journal-title":"Mol. Biol. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1165\/rcmb.2005-0087OC","article-title":"Contribution of TNF-\u03b1 Converting Enzyme and Proteinase-3 to TNF-\u03b1 Processing in Human Alveolar Macrophages","volume":"34","author":"Armstrong","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1083\/jcb.200307137","article-title":"Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands","volume":"164","author":"Sahin","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.bbrc.2010.03.139","article-title":"Distinct role of the intracellular C-terminus for subcellular expression, shedding and function of the murine transmembrane chemokine CX3CL1","volume":"395","author":"Andrzejewski","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3389\/fmicb.2015.00963","article-title":"Pseudomonas Exotoxin A: Optimized by evolution for effective killing","volume":"6","author":"Michalska","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/nmeth.2172","article-title":"TGFalpha shedding assay: An accurate and versatile method for detecting GPCR activation","volume":"9","author":"Inoue","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/35067088","article-title":"Multifunctional strands in tight junctions","volume":"2","author":"Tsukita","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1242\/jcs.00930","article-title":"Junctional adhesion molecules (JAMs): More molecules with dual functions?","volume":"117","author":"Ebnet","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e24783","DOI":"10.4161\/tisb.24783","article-title":"Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis","volume":"1","author":"Nava","year":"2013","journal-title":"Tissue Barriers"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1128\/iai.15.1.138-144.1977","article-title":"Mechanism of action of Pseudomonas aeruginosa exotoxin Aiadenosine diphosphate-ribosylation of mammalian elongation factor 2 in vitro and in vivo","volume":"15","author":"Iglewski","year":"1977","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bolik, J., Krause, F., Stevanovic, M., Gandra\u00df, M., Thomsen, I., Schacht, S.-S., Rieser, E., M\u00fcller, M., Schumacher, N., and Fritsch, J. (2021). Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis. J. Exp. Med., 219.","DOI":"10.1084\/jem.20201039"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Palacios, Y., and Chavez-Galan, L. (2022). Immunosuppressant Therapies in COVID-19: Is the TNF Axis an Alternative?. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050616"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"29406","DOI":"10.18632\/oncotarget.14707","article-title":"Incidence and risk of infections associated with EGFR-TKIs in advanced non-small-cell lung cancer: A-systematic review and meta-analysis of randomized controlled trials","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1164\/rccm.201002-0188OC","article-title":"EGFR Tyrosine Kinase Inhibition Worsens Acute Lung Injury in Mice with Repairing Airway Epithelium","volume":"183","author":"Harada","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/s41419-018-0941-y","article-title":"JAM-A knockdown accelerates the proliferation and migration of human keratinocytes, and improves wound healing in rats via FAK\/Erk signaling","volume":"9","author":"Wang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1007\/s00018-022-04140-5","article-title":"JAM-A interacts with alpha3beta1 integrin and tetraspanins CD151 and CD9 to regulate collective cell migration of polarized epithelial cells","volume":"79","author":"Tholmann","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1182\/blood-2008-04-152330","article-title":"Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases","volume":"113","author":"Koenen","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37459","DOI":"10.1074\/jbc.M305877200","article-title":"Stimulated Shedding of Vascular Cell Adhesion Molecule 1 (VCAM-1) Is Mediated by Tumor Necrosis Factor-\u03b1-converting Enzyme (ADAM 17)","volume":"278","author":"Garton","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1074\/jbc.M510797200","article-title":"Tumor Necrosis Factor-\u03b1-converting Enzyme (TACE\/ADAM-17) Mediates the Ectodomain Cleavage of Intercellular Adhesion Molecule-1 (ICAM-1)","volume":"281","author":"Tsakadze","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.4049\/jimmunol.164.1.427","article-title":"Monocyte Migration Through the Alveolar Epithelial Barrier: Adhesion Molecule Mechanisms and Impact of Chemokines","volume":"164","author":"Rosseau","year":"2000","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00018-019-03184-4","article-title":"Degradome of soluble ADAM10 and ADAM17 metalloproteases","volume":"77","author":"Scharfenberg","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1016\/j.bbamcr.2016.09.002","article-title":"Stimulated release and functional activity of surface expressed metalloproteinase ADAM17 in exosomes","volume":"1863","author":"Groth","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s40168-020-00866-1","article-title":"Skin microbiota analysis-inspired development of novel anti-infectives","volume":"8","author":"Liu","year":"2020","journal-title":"Microbiome"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13036-018-0138-z","article-title":"Inhibition of bacterial toxin recognition of membrane components as an anti-virulence strategy","volume":"13","author":"Krueger","year":"2019","journal-title":"J. Biol. Eng."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.4049\/jimmunol.175.3.1930","article-title":"Bacterial Induction of TNF-\u03b1 Converting Enzyme Expression and IL-6 Receptor \u03b1 Shedding Regulates Airway Inflammatory Signaling","volume":"175","author":"Sokol","year":"2005","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Raoust, E., Balloy, V., Garcia-Verdugo, I., Touqui, L., Ramphal, R., and Chignard, M. (2009). Pseudomonas aeruginosa LPS or Flagellin Are Sufficient to Activate TLR-Dependent Signaling in Murine Alveolar Macrophages and Airway Epithelial Cells. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007259"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1046\/j.1365-2958.1997.4891851.x","article-title":"ExoU expression by Pseudomonas aeruginosa correlates with acute cytotoxicity and epithelial injury","volume":"25","author":"Goranson","year":"1997","journal-title":"Mol. Microbiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S1074-7613(00)80119-3","article-title":"Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components","volume":"11","author":"Takeuchi","year":"1999","journal-title":"Immunity"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1038\/nm.2451","article-title":"A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice","volume":"17","author":"Inoshima","year":"2011","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1091\/mbc.e08-11-1135","article-title":"ADAMs 10 and 17 represent differentially regulated components of a general shedding machinery for membrane proteins such as transforming growth factor alpha, L-selectin, and tumor necrosis factor alpha","volume":"20","author":"Bobe","year":"2009","journal-title":"Mol. Biol. Cell."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S1438-4221(00)80047-8","article-title":"Pseudomonas aeruginosa exoenzyme S, a bifunctional type-III secreted cytotoxin","volume":"290","author":"Barbieri","year":"2000","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6066","DOI":"10.1128\/IAI.68.10.6066-6068.2000","article-title":"Pseudomonas aeruginosa ExoT Is a Rho GTPase-Activating Protein","volume":"68","author":"Krall","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.4049\/jimmunol.0802770","article-title":"Regulation of Mature ADAM17 by Redox Agents for L-Selectin Shedding","volume":"182","author":"Wang","year":"2009","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1042\/BJ20100179","article-title":"Thiol isomerases negatively regulate the cellular shedding activity of ADAM17","volume":"428","author":"Willems","year":"2010","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1189\/jlb.0312112","article-title":"ADAM17 activation in circulating neutrophils following bacterial challenge impairs their recruitment","volume":"92","author":"Long","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"722","DOI":"10.4049\/jimmunol.1302496","article-title":"Smooth Muscle Cells Relay Acute Pulmonary Inflammation via Distinct ADAM17\/ErbB Axes","volume":"192","author":"Dreymueller","year":"2013","journal-title":"J. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/15\/2303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:57:05Z","timestamp":1760140625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/15\/2303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,26]]},"references-count":54,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cells11152303"],"URL":"https:\/\/doi.org\/10.3390\/cells11152303","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,26]]}}}