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Respiratory epithelial cells provide a first line of defense against pulmonary pathogens and play a crucial role in the immune response during pneumonia caused by <jats:italic>Pseudomonas (P<\/jats:italic>.<jats:italic>) aeruginosa<\/jats:italic>, a gram-negative bacterium that expresses flagellin as an important virulence factor. We here sought to determine the role of Dntm3b in respiratory epithelial cells in immune responses elicited by <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic>. <jats:italic>DNMT3B<\/jats:italic> expression was reduced in human bronchial epithelial (BEAS-2B) cells as well as in primary human and mouse bronchial epithelial cells grown in air liquid interface upon exposure to <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic> (PAK). Dnmt3b deficient human bronchial epithelial (BEAS-2B) cells produced more CXCL1, CXCL8 and CCL20 than control cells when stimulated with PAK, flagellin-deficient PAK (PAKflic) or flagellin. Dnmt3b deficiency reduced DNA methylation at exon 1 of <jats:italic>CXCL1<\/jats:italic> and enhanced NF-\u0138B p65 binding to the <jats:italic>CXCL1<\/jats:italic> promoter. Mice with bronchial epithelial Dntm3b deficiency showed increased <jats:italic>Cxcl1<\/jats:italic> mRNA expression in bronchial epithelium and CXCL1 protein release in the airways during pneumonia caused by PAK, which was associated with enhanced neutrophil recruitment and accelerated bacterial clearance; bronchial epithelial Dnmt3b deficiency did not modify responses during pneumonia caused by PAKflic or <jats:italic>Klebsiella pneumoniae<\/jats:italic> (an un-flagellated gram-negative bacterium). Dnmt3b deficiency in type II alveolar epithelial cells did not affect mouse pulmonary defense against PAK infection. These results suggest that bronchial epithelial Dnmt3b impairs host defense during <jats:italic>Pseudomonas<\/jats:italic> induced pneumonia, at least in part, by dampening mucosal responses to flagellin.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009491","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T18:41:21Z","timestamp":1617302481000},"page":"e1009491","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Bronchial epithelial DNA methyltransferase 3b dampens pulmonary immune responses during Pseudomonas aeruginosa infection"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7776-5007","authenticated-orcid":true,"given":"Wanhai","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xanthe","family":"Brands","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"van\u2019t Veer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2472-3014","authenticated-orcid":true,"given":"Alex","family":"F. de Vos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9854-4652","authenticated-orcid":true,"given":"Jean-Claude","family":"Sirard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-6571","authenticated-orcid":true,"given":"Joris","family":"J. 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