Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically
Abstract How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal c...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56379-8 |
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| author | Mingming Zhao Dragana Jankovic Verena M. Link Camila Oliveira Silva Souza Katherine M. Hornick Oyebola Oyesola Yasmine Belkaid Justin Lack Png Loke |
| author_facet | Mingming Zhao Dragana Jankovic Verena M. Link Camila Oliveira Silva Souza Katherine M. Hornick Oyebola Oyesola Yasmine Belkaid Justin Lack Png Loke |
| author_sort | Mingming Zhao |
| collection | DOAJ |
| description | Abstract How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure. |
| format | Article |
| id | doaj-art-613a33578f1d4075ab9d566810927180 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-613a33578f1d4075ab9d5668109271802025-01-26T12:42:48ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-025-56379-8Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigeneticallyMingming Zhao0Dragana Jankovic1Verena M. Link2Camila Oliveira Silva Souza3Katherine M. Hornick4Oyebola Oyesola5Yasmine Belkaid6Justin Lack7Png Loke8Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)Type 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of HealthType 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)NIAID Collaborative Bioinformatics Resource, Integrated Data Sciences Section, Research Technology Branch, Division of Intramural Research, NIAID, NIHType 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of HealthNIAID Collaborative Bioinformatics Resource, Integrated Data Sciences Section, Research Technology Branch, Division of Intramural Research, NIAID, NIHType 2 Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)Abstract How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.https://doi.org/10.1038/s41467-025-56379-8 |
| spellingShingle | Mingming Zhao Dragana Jankovic Verena M. Link Camila Oliveira Silva Souza Katherine M. Hornick Oyebola Oyesola Yasmine Belkaid Justin Lack Png Loke Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically Nature Communications |
| title | Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically |
| title_full | Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically |
| title_fullStr | Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically |
| title_full_unstemmed | Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically |
| title_short | Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically |
| title_sort | genetic variation in il 4 activated tissue resident macrophages determines strain specific synergistic responses to lps epigenetically |
| url | https://doi.org/10.1038/s41467-025-56379-8 |
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