Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis
Abstract Autophagic activation in immune cells, gut microbiota dysbiosis, and metabolic abnormalities have been reported separately as characteristics of systemic lupus erythematosus (SLE). Elucidating the crosstalk among the immune system, commensal microbiota, and metabolites is crucial to underst...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02041-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585515048632320 |
|---|---|
| author | Jiaxuan Chen Quanren Pan Lu Lu Xiaorong Huang Shuting Wang Xiaoxian Liu Jiaqi Lun Xiaowei Xu Hongyong Su Fengbiao Guo Lawei Yang Liuyong You Haiyan Xiao Wenying Luo Hua-feng Liu Qingjun Pan |
| author_facet | Jiaxuan Chen Quanren Pan Lu Lu Xiaorong Huang Shuting Wang Xiaoxian Liu Jiaqi Lun Xiaowei Xu Hongyong Su Fengbiao Guo Lawei Yang Liuyong You Haiyan Xiao Wenying Luo Hua-feng Liu Qingjun Pan |
| author_sort | Jiaxuan Chen |
| collection | DOAJ |
| description | Abstract Autophagic activation in immune cells, gut microbiota dysbiosis, and metabolic abnormalities have been reported separately as characteristics of systemic lupus erythematosus (SLE). Elucidating the crosstalk among the immune system, commensal microbiota, and metabolites is crucial to understanding the pathogenesis of autoimmune diseases. Emerging evidence shows that basophil activation plays a critical role in the pathogenesis of SLE; however, the underlying mechanisms remain largely unknown. Here, we investigated the effects of autophagic inhibition on the pathogenesis of basophils in SLE using Autophagy-related gene 5 (Atg5) knockout (Atg5 −/−) as an autophagic inhibitor. Specifically, we knocked out basophilic Atg5 in vivo to investigate its impact on lupus metabolism. Furthermore, Atg5 −/− basophils were transferred to basophil-depleted MRL/MpJ-Fas lpr (MRL/lpr) mice to study their effect on disease metabolism. Metagenomic and targeted metabolomic sequencing results indicated considerable reduction in the levels of plasma autoantibodies and inflammatory cytokines in the Atg5 −/− basophil transfer group compared with that in the control group. Transplanting Atg5 −/− basophils improved the gut microbiota balance in MRL/lpr mice, increasing the abundance of beneficial bacteria, such as Ligilactobacillus murinus and Faecalitalea rodentium, and reducing that of potentially pathogenic bacteria such as Phocaeicola salanitronis. The transplantation of Atg5-deficient basophils improved lupus symptoms by modulating lipid and amino acid metabolism. This improvement was linked to changes in the gut microbiota, particularly an increase in Ligilactobacillus murinus and Faecalitalea rodentium populations. These microbial shifts are believed to promote the production of beneficial metabolites, such as γ-linolenic acid and oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine, while reducing the levels of harmful metabolites such as arginine. These alterations in the metabolic profile contribute to the alleviation of lupus symptoms. Collectively, these findings reveal a novel role of basophil autophagy in SLE, highlighting its potential as a therapeutic target. |
| format | Article |
| id | doaj-art-a97150e728234df0af058edbe6283f80 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-a97150e728234df0af058edbe6283f802025-01-26T12:44:54ZengBMCCell Communication and Signaling1478-811X2025-01-0123112010.1186/s12964-025-02041-1Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosisJiaxuan Chen0Quanren Pan1Lu Lu2Xiaorong Huang3Shuting Wang4Xiaoxian Liu5Jiaqi Lun6Xiaowei Xu7Hongyong Su8Fengbiao Guo9Lawei Yang10Liuyong You11Haiyan Xiao12Wenying Luo13Hua-feng Liu14Qingjun Pan15Department of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Clinical Laboratory, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical UniversityDepartment of Cellular Biology and Anatomy, James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityDepartment of Nephrology, National Clinical Key Specialty Construction Program, Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Laboratory Medicine Center, Affiliated Hospital of Guangdong Medical UniversityAbstract Autophagic activation in immune cells, gut microbiota dysbiosis, and metabolic abnormalities have been reported separately as characteristics of systemic lupus erythematosus (SLE). Elucidating the crosstalk among the immune system, commensal microbiota, and metabolites is crucial to understanding the pathogenesis of autoimmune diseases. Emerging evidence shows that basophil activation plays a critical role in the pathogenesis of SLE; however, the underlying mechanisms remain largely unknown. Here, we investigated the effects of autophagic inhibition on the pathogenesis of basophils in SLE using Autophagy-related gene 5 (Atg5) knockout (Atg5 −/−) as an autophagic inhibitor. Specifically, we knocked out basophilic Atg5 in vivo to investigate its impact on lupus metabolism. Furthermore, Atg5 −/− basophils were transferred to basophil-depleted MRL/MpJ-Fas lpr (MRL/lpr) mice to study their effect on disease metabolism. Metagenomic and targeted metabolomic sequencing results indicated considerable reduction in the levels of plasma autoantibodies and inflammatory cytokines in the Atg5 −/− basophil transfer group compared with that in the control group. Transplanting Atg5 −/− basophils improved the gut microbiota balance in MRL/lpr mice, increasing the abundance of beneficial bacteria, such as Ligilactobacillus murinus and Faecalitalea rodentium, and reducing that of potentially pathogenic bacteria such as Phocaeicola salanitronis. The transplantation of Atg5-deficient basophils improved lupus symptoms by modulating lipid and amino acid metabolism. This improvement was linked to changes in the gut microbiota, particularly an increase in Ligilactobacillus murinus and Faecalitalea rodentium populations. These microbial shifts are believed to promote the production of beneficial metabolites, such as γ-linolenic acid and oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine, while reducing the levels of harmful metabolites such as arginine. These alterations in the metabolic profile contribute to the alleviation of lupus symptoms. Collectively, these findings reveal a novel role of basophil autophagy in SLE, highlighting its potential as a therapeutic target.https://doi.org/10.1186/s12964-025-02041-1BasophilsAtg5LupusGut microbiotaMetabolismAutoantibodies |
| spellingShingle | Jiaxuan Chen Quanren Pan Lu Lu Xiaorong Huang Shuting Wang Xiaoxian Liu Jiaqi Lun Xiaowei Xu Hongyong Su Fengbiao Guo Lawei Yang Liuyong You Haiyan Xiao Wenying Luo Hua-feng Liu Qingjun Pan Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis Cell Communication and Signaling Basophils Atg5 Lupus Gut microbiota Metabolism Autoantibodies |
| title | Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| title_full | Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| title_fullStr | Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| title_full_unstemmed | Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| title_short | Atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| title_sort | atg5 deficiency in basophils improves metabolism in lupus mice by regulating gut microbiota dysbiosis |
| topic | Basophils Atg5 Lupus Gut microbiota Metabolism Autoantibodies |
| url | https://doi.org/10.1186/s12964-025-02041-1 |
| work_keys_str_mv | AT jiaxuanchen atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT quanrenpan atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT lulu atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT xiaoronghuang atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT shutingwang atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT xiaoxianliu atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT jiaqilun atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT xiaoweixu atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT hongyongsu atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT fengbiaoguo atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT laweiyang atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT liuyongyou atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT haiyanxiao atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT wenyingluo atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT huafengliu atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis AT qingjunpan atg5deficiencyinbasophilsimprovesmetabolisminlupusmicebyregulatinggutmicrobiotadysbiosis |