IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury
Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicil...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1011132/full |
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| author | Atul K. Verma Michael McKelvey Md Bashir Uddin Sunil Palani Meng Niu Christopher Bauer Shengjun Shao Keer Sun Keer Sun |
| author_facet | Atul K. Verma Michael McKelvey Md Bashir Uddin Sunil Palani Meng Niu Christopher Bauer Shengjun Shao Keer Sun Keer Sun |
| author_sort | Atul K. Verma |
| collection | DOAJ |
| description | Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection. |
| first_indexed | 2024-04-11T21:03:47Z |
| format | Article |
| id | doaj.art-4044e6f6530743088bf07fde8eb116e1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T21:03:47Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-4044e6f6530743088bf07fde8eb116e12022-12-22T04:03:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.10111321011132IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injuryAtul K. Verma0Michael McKelvey1Md Bashir Uddin2Sunil Palani3Meng Niu4Christopher Bauer5Shengjun Shao6Keer Sun7Keer Sun8Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Experimental Pathology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, United StatesDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United StatesDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United StatesAcute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1011132/fullAcute lung injurycytokine storminfluenza A virusmethicillin-resistant Staphylococcus aureuscoinfection |
| spellingShingle | Atul K. Verma Michael McKelvey Md Bashir Uddin Sunil Palani Meng Niu Christopher Bauer Shengjun Shao Keer Sun Keer Sun IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury Frontiers in Immunology Acute lung injury cytokine storm influenza A virus methicillin-resistant Staphylococcus aureus coinfection |
| title | IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| title_full | IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| title_fullStr | IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| title_full_unstemmed | IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| title_short | IFN-γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| title_sort | ifn γ transforms the transcriptomic landscape and triggers myeloid cell hyperresponsiveness to cause lethal lung injury |
| topic | Acute lung injury cytokine storm influenza A virus methicillin-resistant Staphylococcus aureus coinfection |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1011132/full |
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