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Here, we show by single-cell RNA sequencing an increase in\n                    <jats:italic>Pparg<\/jats:italic>\n                    gene expression in lung macrophages from mice exposed to cadmium and\/or infected with\n                    <jats:italic>Streptococcus<\/jats:italic>\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    . However, the heavy metal cadmium or infection mediated an inhibitory posttranslational modification of peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) to exacerbate LRTIs. Cadmium and infection increased ERK activation to regulate PPAR\u03b3 degradation in monocyte-derived macrophages. Mice harboring a conditional deletion of\n                    <jats:italic>Pparg<\/jats:italic>\n                    in monocyte-derived macrophages had more severe\n                    <jats:italic>S<\/jats:italic>\n                    .\n                    <jats:italic>pneumoniae<\/jats:italic>\n                    infection after cadmium exposure, showed greater lung injury, and had increased mortality. Inhibition of ERK activation with BVD-523 protected mice from lung injury after cadmium exposure or infection. Moreover, individuals residing in areas of high air cadmium levels had increased cadmium concentration in their bronchoalveolar lavage (BAL) fluid, increased barrier dysfunction, and showed PPAR\u03b3 inhibition that was mediated, at least in part, by ERK activation in isolated BAL cells. These observations suggest that impaired activation of PPAR\u03b3 in monocyte-derived macrophages exacerbates lung injury and the severity of LRTIs.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.166608","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T12:01:21Z","timestamp":1678968081000},"source":"Crossref","is-referenced-by-count":16,"title":["Impaired PPAR\u03b3 activation by cadmium exacerbates infection-induced lung injury"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7238-7986","authenticated-orcid":true,"given":"Jennifer L.","family":"Larson-Casey","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7201-4212","authenticated-orcid":true,"given":"Shanrun","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9049-4275","authenticated-orcid":true,"given":"Jennifer M.","family":"Pyles","sequence":"additional","affiliation":[{"name":"Department of Radiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0090-0191","authenticated-orcid":true,"given":"Suzanne E.","family":"Lapi","sequence":"additional","affiliation":[{"name":"Department of Radiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Saleem","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veena B.","family":"Antony","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Lora","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0981-169X","authenticated-orcid":true,"given":"David K.","family":"Crossman","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6002-4715","authenticated-orcid":true,"given":"A. 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