FcRn regulates NLRP3 inflammasome and MHC Ⅱ/CD80 to promote podocyte injury in lupus nephritis
10.3969/j.issn.1000-484X.2025.01.002
- VernacularTitle:FcRn调控NLRP3炎性小体及MHC Ⅱ、CD80促进狼疮肾炎足细胞损伤
- Author:
Rong FU
1
;
Zeying LIN
1
;
Yongbao HUO
1
Author Information
1. 广州医科大学附属第二医院风湿免疫科,广州 510260
- Publication Type:Journal Article
- Keywords:
Podocyte;
Antigen presentation;
FcRn;
NLRP3 inflammasome
- From:
Chinese Journal of Immunology
2025;41(1):11-18
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore whether anti-dsDNA antibodies can activate podocyte NLRP3 inflammasomes through FcRn,enhance the antigen-presenting function of podocytes,and promote podocyte damage.Methods:Kidney biopsies from lupus nephritis(LN)patients and lupus model mice were collected.Immunofluorescence was used to detect podocyte MHC Ⅱ,CD80,and FcRn levels.The NLRP3 inhibitor MCC950 was used to intervene in lupus model mice(MRL/lpr),and immunofluorescence was per-formed to assess changes in glomerular MHC Ⅱ and CD80 expressions.Podocytes pretreated with MCC950 were stimulated with anti-dsDNA antibodies,and Western blot was used to measure MHC Ⅱ and CD80 expression.FcRn was knocked down in podocytes using siRNA,and after stimulation with anti-dsDNA antibodies,Western blot was conducted to evaluate NLRP3 and caspase-1 p20 expres-sion levels.CD4+T cells from peripheral blood of SLE patients were sorted and co-cultured with podocytes pretreated with serum from SLE patients,and flow cytometry was used to analyze the proportions of IFN-γ+CD4+T cells and IL-17+CD4+T cells.Immunofluores-cence was used to observe the cytoskeletal changes in podocytes.Results:Podocytes from LN patients and lupus model mice ex-pressed high levels of MHC Ⅱ,CD80,and FcRn.MCC950 intervention significantly reduced MHC Ⅱ and CD80 levels in podocytes of MRL/lpr mice.Anti-dsDNA antibodies induced elevated MHC Ⅱ and CD80 expression in podocytes,which were reduced by NLRP3 inhibitor MCC950(P<0.05).Knockdown of FcRn in podocytes resulted in significant decreases in NLRP3 expression and active cas-pase-1 p20 levels(P<0.05).Co-culturing SLE patient CD4+T cells with podocytes pretreated with SLE patient serum led to a signifi-cant increase in the proportion of IFN-γ+CD4+T cells(P<0.05).There were notable changes in the podocyte cytoskeleton,including a significant reduction in stress fibers and cellular morphological remodeling.Conclusion:Anti-dsDNA antibodies can activate podo-cyte NLRP3 inflammasomes via FcRn,enhancing the antigen-presenting function of podocytes.The activated CD4+T cells further con-tribute to the remodeling of podocyte cytoskeleton.
