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IL-10 plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the present study, we investigated the role of IL-10 in acute lung injury induced by influenza A virus and methicillin-resistant Staphylococcus aureus coinfection. This unique coinfection model resembles patients with acute pneumonia undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor gene-deficient mice, as well as in vivo neutralizing antibodies, we show that IL-10 deficiency promotes IFN-\u03b3\u2013dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-\u03b3 neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-\u03b3\/TNF-\u03b1 hyperproduction and acute mortality. Importantly, this antiinflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and acute respiratory distress syndrome pathogenesis by counteracting the IFN-\u03b3 response.<\/jats:p>","DOI":"10.1165\/rcmb.2023-0437oc","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T15:30:45Z","timestamp":1712244645000},"page":"110-120","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":22,"title":["IL-10 Counteracts IFN-\u03b3 to Alleviate Acute Lung Injury in a Viral-Bacterial Superinfection Model"],"prefix":"10.1093","volume":"71","author":[{"given":"Michael","family":"McKelvey","sequence":"first","affiliation":[{"name":"Department of Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0045-9669","authenticated-orcid":false,"given":"Md Bashir","family":"Uddin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Palani","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9702-9584","authenticated-orcid":false,"given":"Keer","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,1]]},"reference":[{"key":"2026012204192186000_bib1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1542\/peds.2008-1336","article-title":"Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection","volume":"122","author":"Finelli","year":"2008","journal-title":"Pediatrics"},{"key":"2026012204192186000_bib2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jcv.2016.04.008","article-title":"Bacterial and viral co-infections complicating severe influenza: incidence and impact among 507 US patients, 2013-14","volume":"80","author":"Shah","year":"2016","journal-title":"J Clin Virol"},{"key":"2026012204192186000_bib3","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1007\/s00134-020-06292-z","article-title":"Pulmonary infections complicating ARDS","volume":"46","author":"Luyt","year":"2020","journal-title":"Intensive Care Med"},{"key":"2026012204192186000_bib4","doi-asserted-by":"crossref","first-page":"e321","DOI":"10.1016\/j.ijid.2012.01.003","article-title":"Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza","volume":"16","author":"Metersky","year":"2012","journal-title":"Int J Infect Dis"},{"key":"2026012204192186000_bib5","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1007\/s00134-020-06299-6","article-title":"Current and evolving standards of care for patients with ARDS","volume":"46","author":"Menk","year":"2020","journal-title":"Intensive Care Med"},{"key":"2026012204192186000_bib6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s12024-021-00414-9","article-title":"Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1\u03b2, IL-6, IL-15 and TNF-\u03b1","volume":"18","author":"Frisoni","year":"2022","journal-title":"Forensic Sci Med Pathol"},{"key":"2026012204192186000_bib7","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/ng.221","article-title":"Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility","volume":"40","author":"Franke","year":"2008","journal-title":"Nat Genet"},{"key":"2026012204192186000_bib8","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.3390\/jcm12113713","article-title":"Genetic determinants of the acute respiratory distress syndrome","volume":"12","author":"Suarez-Pajes","year":"2023","journal-title":"J Clin Med"},{"key":"2026012204192186000_bib9","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1164\/rccm.201702-0405CP","article-title":"Fifty years of research in ARDS. 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