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We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions and that elevated CO\n                    <jats:sub>2<\/jats:sub>\n                    increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AM\u00d8s). We also show that zinc finger homeobox 3 (Zfhx3) \u2014 a mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    \u2014 is expressed in mouse and human macrophages. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AM\u00d8s and decreased viral replication, inflammatory lung injury, and mortality in hypercapnic mice infected with influenza A virus. To our knowledge, our results establish Zfhx3 as the first known mammalian mediator of CO\n                    <jats:sub>2<\/jats:sub>\n                    effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.170316","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T12:00:22Z","timestamp":1705406422000},"source":"Crossref","is-referenced-by-count":9,"title":["Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-4560","authenticated-orcid":true,"given":"S. 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