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One reason for this is age\u2010dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age\u2010related defects in AM were sufficient to increase the susceptibility to <jats:italic>Streptococcus pneumoniae<\/jats:italic>, a Gram\u2010positive bacterium and the leading cause of community\u2010acquired pneumonia. MAPK phosphorylation arrays using AM lysates from young and aged wild\u2010type (WT) and TNF knockout (KO) mice revealed multilevel TNF\u2010mediated suppression of kinase activity in aged mice. RNAseq analyses of AM validated the suppression of MAPK signaling as a consequence of TNF during aging. Two regulatory phosphatases that suppress MAPK signaling, <jats:italic>Dusp1<\/jats:italic> and <jats:italic>Ptprs<\/jats:italic>, were confirmed to be upregulated with age and as a result of TNF exposure both ex\u00a0vivo and in\u00a0vitro. Dusp1 is known to be responsible for glucocorticoid\u2010mediated immune suppression, and dexamethasone treatment increased <jats:italic>Dusp1<\/jats:italic> and <jats:italic>Ptprs<\/jats:italic> expression in cells and recapitulated the ADMD phenotype. In young mice, treatment with dexamethasone increased the levels of <jats:italic>Dusp1<\/jats:italic> and <jats:italic>Ptprs<\/jats:italic> and their susceptibility to infection. TNF\u2010neutralizing antibody reduced <jats:italic>Dusp1<\/jats:italic> and <jats:italic>Ptprs<\/jats:italic> levels in AM from aged mice and reduced pneumonia severity following bacterial challenge. We conclude that chronic exposure to TNF increases the expression of the glucocorticoid\u2010associated MAPK signaling suppressors, <jats:italic>Dusp1<\/jats:italic> and <jats:italic>Ptprs,<\/jats:italic> which inhibits AM activation and increases susceptibility to bacterial pneumonia in older adults.<\/jats:p>","DOI":"10.1111\/acel.14133","type":"journal-article","created":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T06:50:21Z","timestamp":1709967021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Chronic TNF exposure induces glucocorticoid\u2010like immunosuppression in the alveolar macrophages of aged mice that enhances their susceptibility to pneumonia"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2730-8163","authenticated-orcid":false,"given":"Katherine L.","family":"Kruckow","sequence":"first","affiliation":[{"name":"Department of Microbiology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Microbiology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elnur","family":"Shayhidin","sequence":"additional","affiliation":[{"name":"Firestone Institute for Respiratory Health St. Joseph's Healthcare Hamilton  Hamilton Ontario Canada"},{"name":"The M.G. 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