Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function
Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterati...
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Military Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40779-023-00462-y |
| _version_ | 1827917065060614144 |
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| author | Ren-Qi Yao Peng-Yue Zhao Zhi-Xuan Li Yu-Yang Liu Li-Yu Zheng Yu Duan Lu Wang Rong-Li Yang Hong-Jun Kang Ji-Wei Hao Jing-Yan Li Ning Dong Yao Wu Xiao-Hui Du Feng Zhu Chao Ren Guo-Sheng Wu Zhao-Fan Xia Yong-Ming Yao |
| author_facet | Ren-Qi Yao Peng-Yue Zhao Zhi-Xuan Li Yu-Yang Liu Li-Yu Zheng Yu Duan Lu Wang Rong-Li Yang Hong-Jun Kang Ji-Wei Hao Jing-Yan Li Ning Dong Yao Wu Xiao-Hui Du Feng Zhu Chao Ren Guo-Sheng Wu Zhao-Fan Xia Yong-Ming Yao |
| author_sort | Ren-Qi Yao |
| collection | DOAJ |
| description | Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis. |
| first_indexed | 2024-03-13T03:23:25Z |
| format | Article |
| id | doaj.art-a8f793824e8c44ee83a53b4acfbb846e |
| institution | Directory Open Access Journal |
| issn | 2054-9369 |
| language | English |
| last_indexed | 2024-03-13T03:23:25Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj.art-a8f793824e8c44ee83a53b4acfbb846e2023-06-25T11:12:15ZengBMCMilitary Medical Research2054-93692023-06-0110112010.1186/s40779-023-00462-ySingle-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive functionRen-Qi Yao0Peng-Yue Zhao1Zhi-Xuan Li2Yu-Yang Liu3Li-Yu Zheng4Yu Duan5Lu Wang6Rong-Li Yang7Hong-Jun Kang8Ji-Wei Hao9Jing-Yan Li10Ning Dong11Yao Wu12Xiao-Hui Du13Feng Zhu14Chao Ren15Guo-Sheng Wu16Zhao-Fan Xia17Yong-Ming Yao18Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalDepartment of Neurosurgery, the First Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalDepartment of Critical Care Medicine, the First Medical Center of Chinese PLA General HospitalIntensive Care Unit, Dalian Municipal Central Hospital Affiliated Dalian University of TechnologyDepartment of Critical Care Medicine, the First Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalDepartment of Emergency, the Second Hospital of Hebei Medical UniversityTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalDepartment of General Surgery, the First Medical Center of Chinese PLA General HospitalDepartment of Burn Surgery, the First Affiliated Hospital of Naval Medical UniversityDepartment of Pulmonary and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical UniversityDepartment of Burn Surgery, the First Affiliated Hospital of Naval Medical UniversityDepartment of Burn Surgery, the First Affiliated Hospital of Naval Medical UniversityTranslational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General HospitalAbstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.https://doi.org/10.1186/s40779-023-00462-ySingle-cell analysisSepsisImmunosuppressionS100AHuman leukocyte antigen DR (HLA-DR)Monocytes |
| spellingShingle | Ren-Qi Yao Peng-Yue Zhao Zhi-Xuan Li Yu-Yang Liu Li-Yu Zheng Yu Duan Lu Wang Rong-Li Yang Hong-Jun Kang Ji-Wei Hao Jing-Yan Li Ning Dong Yao Wu Xiao-Hui Du Feng Zhu Chao Ren Guo-Sheng Wu Zhao-Fan Xia Yong-Ming Yao Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function Military Medical Research Single-cell analysis Sepsis Immunosuppression S100A Human leukocyte antigen DR (HLA-DR) Monocytes |
| title | Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function |
| title_full | Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function |
| title_fullStr | Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function |
| title_full_unstemmed | Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function |
| title_short | Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function |
| title_sort | single cell transcriptome profiling of sepsis identifies hla dr low s100a high monocytes with immunosuppressive function |
| topic | Single-cell analysis Sepsis Immunosuppression S100A Human leukocyte antigen DR (HLA-DR) Monocytes |
| url | https://doi.org/10.1186/s40779-023-00462-y |
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