Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells
Abstract Background Renal CD8+ tissue-resident memory T (TRM) cells display prolonged survival and activity in lupus nephritis (LN), exacerbating renal pathology. NLRP3 regulates the T cell response. This study explored the impact of NLRP3 inflammasome activity on the regulatory functions of TRM cel...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-05951-9 |
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| author | Yimei Lai Lili Zhuang Jieying Zhu Shuang Wang Chaohuan Guo Binfeng Chen Jin Li Jia Shi Mengyuan Li Niansheng Yang Mianjing Zhou |
| author_facet | Yimei Lai Lili Zhuang Jieying Zhu Shuang Wang Chaohuan Guo Binfeng Chen Jin Li Jia Shi Mengyuan Li Niansheng Yang Mianjing Zhou |
| author_sort | Yimei Lai |
| collection | DOAJ |
| description | Abstract Background Renal CD8+ tissue-resident memory T (TRM) cells display prolonged survival and activity in lupus nephritis (LN), exacerbating renal pathology. NLRP3 regulates the T cell response. This study explored the impact of NLRP3 inflammasome activity on the regulatory functions of TRM cells in LN. Methods NLRP3 inflammasome activity in renal CD8+ TRM cells from lupus-prone MRL/lpr mice and in vitro induced human CD8+CD103+ T cells was assessed by quantifying NLRP3, caspase-1, gasdermin D (GSDMD), and IL-1β levels using flow cytometry, ELISA, and western blotting analysis. The specific NLRP3 inhibitor MCC950, caspase-1 inhibitor Ac-YVAD-cmk, and NF-κB inhibitor JSH23 were utilized to delineate the role of NLRP3 in modulating the pathogenicity of CD8+ TRM cells in LN. Results Activation of the NLRP3 inflammasome was confirmed in renal CD8+CD69+CD103+ TRM cells derived from mice with LN and in vitro-induced human CD8+CD103+ TRM-like cells. MCC950 curtailed the infiltration and activity of CD8+CD69+CD103+ TRM cells and enhanced renal outcomes. MCC950 also suppressed the maturation and functional capabilities of CD8+CD103+ T cells in a manner reliant on inflammasome activity in vitro. IL-1β promoted the expression of TGF-βRII in CD8+ T cells via the NF-κB pathway. Conclusions NLRP3 inflammasome activity in renal CD8+CD69+CD103+ TRM cells contributes to LN pathogenesis by regulating cell differentiation and effector functions. Therapeutically targeting the NLRP3 inflammasome could significantly mitigate CD8+CD69+CD103+ TRM cell-mediated renal damage in LN. |
| format | Article |
| id | doaj-art-8d8b8e955a6b44d99b30bc79e342db0c |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-8d8b8e955a6b44d99b30bc79e342db0c2024-12-29T12:45:13ZengBMCJournal of Translational Medicine1479-58762024-12-0122111810.1186/s12967-024-05951-9Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cellsYimei Lai0Lili Zhuang1Jieying Zhu2Shuang Wang3Chaohuan Guo4Binfeng Chen5Jin Li6Jia Shi7Mengyuan Li8Niansheng Yang9Mianjing Zhou10Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rheumatology, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract Background Renal CD8+ tissue-resident memory T (TRM) cells display prolonged survival and activity in lupus nephritis (LN), exacerbating renal pathology. NLRP3 regulates the T cell response. This study explored the impact of NLRP3 inflammasome activity on the regulatory functions of TRM cells in LN. Methods NLRP3 inflammasome activity in renal CD8+ TRM cells from lupus-prone MRL/lpr mice and in vitro induced human CD8+CD103+ T cells was assessed by quantifying NLRP3, caspase-1, gasdermin D (GSDMD), and IL-1β levels using flow cytometry, ELISA, and western blotting analysis. The specific NLRP3 inhibitor MCC950, caspase-1 inhibitor Ac-YVAD-cmk, and NF-κB inhibitor JSH23 were utilized to delineate the role of NLRP3 in modulating the pathogenicity of CD8+ TRM cells in LN. Results Activation of the NLRP3 inflammasome was confirmed in renal CD8+CD69+CD103+ TRM cells derived from mice with LN and in vitro-induced human CD8+CD103+ TRM-like cells. MCC950 curtailed the infiltration and activity of CD8+CD69+CD103+ TRM cells and enhanced renal outcomes. MCC950 also suppressed the maturation and functional capabilities of CD8+CD103+ T cells in a manner reliant on inflammasome activity in vitro. IL-1β promoted the expression of TGF-βRII in CD8+ T cells via the NF-κB pathway. Conclusions NLRP3 inflammasome activity in renal CD8+CD69+CD103+ TRM cells contributes to LN pathogenesis by regulating cell differentiation and effector functions. Therapeutically targeting the NLRP3 inflammasome could significantly mitigate CD8+CD69+CD103+ TRM cell-mediated renal damage in LN.https://doi.org/10.1186/s12967-024-05951-9Lupus nephritisNLRP3 inflammasomeCD8+ tissue-resident memory cellsIL-1β |
| spellingShingle | Yimei Lai Lili Zhuang Jieying Zhu Shuang Wang Chaohuan Guo Binfeng Chen Jin Li Jia Shi Mengyuan Li Niansheng Yang Mianjing Zhou Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells Journal of Translational Medicine Lupus nephritis NLRP3 inflammasome CD8+ tissue-resident memory cells IL-1β |
| title | Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells |
| title_full | Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells |
| title_fullStr | Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells |
| title_full_unstemmed | Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells |
| title_short | Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8+CD69+CD103+ TRM cells |
| title_sort | novel approach to alleviate lupus nephritis targeting the nlrp3 inflammasome in cd8 cd69 cd103 trm cells |
| topic | Lupus nephritis NLRP3 inflammasome CD8+ tissue-resident memory cells IL-1β |
| url | https://doi.org/10.1186/s12967-024-05951-9 |
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