Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context
Summary: Background: HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependen...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422005643 |
| _version_ | 1811320017169416192 |
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| author | Qing Xiao Liting Yan Junyan Han Siyuan Yang Yunxia Tang Qun Li Xiaojie Lao Zhen Chen Jiang Xiao Hongxin Zhao Fengting Yu Fujie Zhang |
| author_facet | Qing Xiao Liting Yan Junyan Han Siyuan Yang Yunxia Tang Qun Li Xiaojie Lao Zhen Chen Jiang Xiao Hongxin Zhao Fengting Yu Fujie Zhang |
| author_sort | Qing Xiao |
| collection | DOAJ |
| description | Summary: Background: HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood. Methods: Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed. Findings: We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells. Interpretation: Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs. Funding: This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126). |
| first_indexed | 2024-04-13T12:52:09Z |
| format | Article |
| id | doaj.art-76d55baa3c664a2ba3087fe971a78253 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-13T12:52:09Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-76d55baa3c664a2ba3087fe971a782532022-12-22T02:46:10ZengElsevierEBioMedicine2352-39642022-12-0186104382Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in contextQing Xiao0Liting Yan1Junyan Han2Siyuan Yang3Yunxia Tang4Qun Li5Xiaojie Lao6Zhen Chen7Jiang Xiao8Hongxin Zhao9Fengting Yu10Fujie Zhang11Beijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Infectious Disease Department, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, ChinaBeijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, China; Corresponding author. Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.Beijing Ditan Hospital, Capital Medical University, Beijing, China; Clinical Center for HIV/AIDS, Capital Medical University, Beijing, China; Corresponding author. Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.Summary: Background: HIV immune non-responders (INRs) are described as a failure to reestablish a pool of CD4+ T lymphocytes (CD4 cells) after antiretroviral therapy (ART), which is related to poor clinical results. Ferroptosis is a newly discovered form of cell death characterised by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS). The mechanism of unrecoverable CD4 cells in INRs and whether ferroptosis plays a role are not fully understood. Methods: Ninety-two people living with HIV (PLHIVs) who experienced four-year ART with sustained viral suppression, including 27 INRs, 34 partial responders (PRs), and 31 complete responders (CRs); and 26 uninfected control participants (UCs) were analysed for 16 immune parameters with flow cytometry. Then plasma lipid, iron and oxidation, and antioxidant indicators were detected by ELISA, and CD4 cells were sorted out and visualised under transmission electron microscopy. Finally, ferroptosis inhibitors were added, and alterations in CD4 cell phenotype and function were observed. Findings: We found decreased recent thymic emigrants (RTE), over-activation and over-proliferation phenotypes, diminished killing function, decreased IL-7R and more severe inflammation; increased lipid peroxidation in the mitochondria and disruptions of the mitochondrial structure, showing typical features of ferroptosis in CD4 cells in INRs. Additionally, ferroptosis inhibitors could reduce inflammation and repair mitochondrial damage. Meanwhile, ELISA results showed increased plasma free fatty acids (FFA) and an imbalance of oxidative and antioxidant systems in INRs. Flow cytometry results displayed alterations of both transferrin receptor (CD71) and lipid transporter (CD36) expressions on the surface of CD4 cells. Mechanistically, there was a stronger correlation between CD36 expression and mitochondrial lipid peroxidation production, ferroptosis makers, and inflammation indicators; while amino acid transporter (CD98) was more related to killing functions; and CD71 was more closely related to activation status in CD4 cells. Interpretation: Cellular metabolism was closely correlated with its diverse functions in INRs. Ferroptosis was observed in CD4 cells of INRs, and inhibiting ferroptosis through modulating mitochondrial disorders and inflammation may offer an alternative immunological strategy for reinvigorating CD4 cells in INRs. Funding: This research was supported by the 13th Five-year Plan, Ministry of Science and Technology of China (2018ZX10302-102), Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20191802), and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX202126).http://www.sciencedirect.com/science/article/pii/S2352396422005643Human immunodeficiency virus (HIV)Poor immune reconstitution (PIR)Immune non-responder (INR)FerroptosisMetabolismInflammation |
| spellingShingle | Qing Xiao Liting Yan Junyan Han Siyuan Yang Yunxia Tang Qun Li Xiaojie Lao Zhen Chen Jiang Xiao Hongxin Zhao Fengting Yu Fujie Zhang Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context EBioMedicine Human immunodeficiency virus (HIV) Poor immune reconstitution (PIR) Immune non-responder (INR) Ferroptosis Metabolism Inflammation |
| title | Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context |
| title_full | Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context |
| title_fullStr | Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context |
| title_full_unstemmed | Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context |
| title_short | Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-respondersResearch in context |
| title_sort | metabolism dependent ferroptosis promotes mitochondrial dysfunction and inflammation in cd4 t lymphocytes in hiv infected immune non respondersresearch in context |
| topic | Human immunodeficiency virus (HIV) Poor immune reconstitution (PIR) Immune non-responder (INR) Ferroptosis Metabolism Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422005643 |
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