Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model
BackgroundHydroxychloroquine (HCQ) is a frontline treatment for autoimmune diseases, including rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE), due to its potent immunomodulatory properties. Efferocytosis, a crucial process for tissue homeostasis by transmitting immu...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524315/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850101928935030784 |
|---|---|
| author | Shin-Yi Liu Shin-Yi Liu Shin-Yi Liu Yung-Ju Yeh Yung-Ju Yeh Ting-Yin Xue Ting-Yin Xue Fei-Hung Hsieh Fei-Hung Hsieh Ya-Wun Wu Ya-Wun Wu Meng-Zhen Wu Meng-Zhen Wu Wei-Jing Li Wei-Jing Li Jun-Chieh J. Tsay Jun-Chieh J. Tsay Shu-Yao Tsai Chung-Ming Huang Chung-Ming Huang Hen-Hong Chang Hen-Hong Chang Hui-Chen Chen Chun-Ping Lin Gregory J. Tsay Gregory J. Tsay Gregory J. Tsay |
| author_facet | Shin-Yi Liu Shin-Yi Liu Shin-Yi Liu Yung-Ju Yeh Yung-Ju Yeh Ting-Yin Xue Ting-Yin Xue Fei-Hung Hsieh Fei-Hung Hsieh Ya-Wun Wu Ya-Wun Wu Meng-Zhen Wu Meng-Zhen Wu Wei-Jing Li Wei-Jing Li Jun-Chieh J. Tsay Jun-Chieh J. Tsay Shu-Yao Tsai Chung-Ming Huang Chung-Ming Huang Hen-Hong Chang Hen-Hong Chang Hui-Chen Chen Chun-Ping Lin Gregory J. Tsay Gregory J. Tsay Gregory J. Tsay |
| author_sort | Shin-Yi Liu |
| collection | DOAJ |
| description | BackgroundHydroxychloroquine (HCQ) is a frontline treatment for autoimmune diseases, including rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE), due to its potent immunomodulatory properties. Efferocytosis, a crucial process for tissue homeostasis by transmitting immune-suppressive signals, is frequently impaired in SLE. We hypothesized HCQ enhances efferocytosis and mediates anti-inflammatory effects.MethodsA pristane-induced lupus (PIL) mouse model was used to assess the preventive efficacy of HCQ by measuring inflammatory cytokine levels, autoantibody titers, and lupus nephritis severity. Efferocytosis in HCQ-treated macrophages was quantified following co-incubation with apoptotic cells and the expression levels of TAM family receptors post-HCQ stimulation were analyzed in vitro and in vivo. The role of MerTK on HCQ-modulated inflammation was revealed by MerTK inhibitor UNC2025.ResultsLong-term HCQ treatment in PIL mice significantly reduced disease activity. HCQ treatment enhanced efferocytosis in RAW264.7 cells, while peritoneal macrophages from HCQ-treated mice showed increased efferocytotic capacity compare to PIL mice. Additionally, HCQ upregulated the expression of the TAM receptor MerTK and Gas6 on macrophages, restoring MerTK levels suppressed by pristane in the spleen of PIL mice. Inhibition of MerTK signaling by UNC2025 mitigated HCQ-mediated enhancements in efferocytosis and reversed the reduction in inflammatory mediators including IL-6 and IFN-α. HCQ-induced anti-inflammatory markers, such as PPARγ, LXR, and IL-10, were also alleviated upon MerTK blockade.ConclusionThis study provides robust in vitro and in vivo evidence that HCQ promotes macrophage efferocytosis and anti-inflammatory reprogramming via MerTK/Gas6 signaling, offering insights into potential therapeutic mechanisms in SLE management. |
| format | Article |
| id | doaj-art-1ae774fb19e341d9b521b8b7b11bc033 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-1ae774fb19e341d9b521b8b7b11bc0332025-08-20T02:39:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15243151524315Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse modelShin-Yi Liu0Shin-Yi Liu1Shin-Yi Liu2Yung-Ju Yeh3Yung-Ju Yeh4Ting-Yin Xue5Ting-Yin Xue6Fei-Hung Hsieh7Fei-Hung Hsieh8Ya-Wun Wu9Ya-Wun Wu10Meng-Zhen Wu11Meng-Zhen Wu12Wei-Jing Li13Wei-Jing Li14Jun-Chieh J. Tsay15Jun-Chieh J. Tsay16Shu-Yao Tsai17Chung-Ming Huang18Chung-Ming Huang19Hen-Hong Chang20Hen-Hong Chang21Hui-Chen Chen22Chun-Ping Lin23Gregory J. Tsay24Gregory J. Tsay25Gregory J. Tsay26Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanDivision of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, NY, United StatesDivision of Pulmonary and Critical Care Medicine, Veterans Administration (VA) New York Harbor Healthcare System, New York, NY, United StatesDepartment of Food Nutrition and Health Biotechnology, Asia University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanCollege of Medicine, China Medical University, Taichung, TaiwanDepartment of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan0Graduate Institute of Integrated Medicine, Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan1Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, TaiwanDepartment of Food Nutrition and Health Biotechnology, Asia University, Taichung, TaiwanResearch and Development Center for Immunology, China Medical University, Taichung, TaiwanDivision of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, TaiwanCollege of Medicine, China Medical University, Taichung, TaiwanBackgroundHydroxychloroquine (HCQ) is a frontline treatment for autoimmune diseases, including rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus (SLE), due to its potent immunomodulatory properties. Efferocytosis, a crucial process for tissue homeostasis by transmitting immune-suppressive signals, is frequently impaired in SLE. We hypothesized HCQ enhances efferocytosis and mediates anti-inflammatory effects.MethodsA pristane-induced lupus (PIL) mouse model was used to assess the preventive efficacy of HCQ by measuring inflammatory cytokine levels, autoantibody titers, and lupus nephritis severity. Efferocytosis in HCQ-treated macrophages was quantified following co-incubation with apoptotic cells and the expression levels of TAM family receptors post-HCQ stimulation were analyzed in vitro and in vivo. The role of MerTK on HCQ-modulated inflammation was revealed by MerTK inhibitor UNC2025.ResultsLong-term HCQ treatment in PIL mice significantly reduced disease activity. HCQ treatment enhanced efferocytosis in RAW264.7 cells, while peritoneal macrophages from HCQ-treated mice showed increased efferocytotic capacity compare to PIL mice. Additionally, HCQ upregulated the expression of the TAM receptor MerTK and Gas6 on macrophages, restoring MerTK levels suppressed by pristane in the spleen of PIL mice. Inhibition of MerTK signaling by UNC2025 mitigated HCQ-mediated enhancements in efferocytosis and reversed the reduction in inflammatory mediators including IL-6 and IFN-α. HCQ-induced anti-inflammatory markers, such as PPARγ, LXR, and IL-10, were also alleviated upon MerTK blockade.ConclusionThis study provides robust in vitro and in vivo evidence that HCQ promotes macrophage efferocytosis and anti-inflammatory reprogramming via MerTK/Gas6 signaling, offering insights into potential therapeutic mechanisms in SLE management.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524315/fullHCQefferocytosisMERTKinflammationSLE |
| spellingShingle | Shin-Yi Liu Shin-Yi Liu Shin-Yi Liu Yung-Ju Yeh Yung-Ju Yeh Ting-Yin Xue Ting-Yin Xue Fei-Hung Hsieh Fei-Hung Hsieh Ya-Wun Wu Ya-Wun Wu Meng-Zhen Wu Meng-Zhen Wu Wei-Jing Li Wei-Jing Li Jun-Chieh J. Tsay Jun-Chieh J. Tsay Shu-Yao Tsai Chung-Ming Huang Chung-Ming Huang Hen-Hong Chang Hen-Hong Chang Hui-Chen Chen Chun-Ping Lin Gregory J. Tsay Gregory J. Tsay Gregory J. Tsay Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model Frontiers in Immunology HCQ efferocytosis MERTK inflammation SLE |
| title | Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model |
| title_full | Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model |
| title_fullStr | Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model |
| title_full_unstemmed | Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model |
| title_short | Hydroxychloroquine enhances efferocytosis and modulates inflammation via MerTK/Gas6 signaling in a pristane-induced lupus mouse model |
| title_sort | hydroxychloroquine enhances efferocytosis and modulates inflammation via mertk gas6 signaling in a pristane induced lupus mouse model |
| topic | HCQ efferocytosis MERTK inflammation SLE |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1524315/full |
| work_keys_str_mv | AT shinyiliu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT shinyiliu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT shinyiliu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT yungjuyeh hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT yungjuyeh hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT tingyinxue hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT tingyinxue hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT feihunghsieh hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT feihunghsieh hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT yawunwu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT yawunwu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT mengzhenwu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT mengzhenwu hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT weijingli hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT weijingli hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT junchiehjtsay hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT junchiehjtsay hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT shuyaotsai hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT chungminghuang hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT chungminghuang hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT henhongchang hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT henhongchang hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT huichenchen hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT chunpinglin hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT gregoryjtsay hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT gregoryjtsay hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel AT gregoryjtsay hydroxychloroquineenhancesefferocytosisandmodulatesinflammationviamertkgas6signalinginapristaneinducedlupusmousemodel |