Rong Fu,Afroditi Boulougoura,Shuilian Yu,Hao Li,Wenliang Pan,Yushiro Endo,Rhea Bhargava,Abhiyan Satyam,Vivek Kasinath,Jarrat Jordan,Nandan Padmanabha,Maria G Tsokos,Reza Abdi,George C Tsokos
{"title":"Interleukin-23 receptor deficiency in podocytes averts the development of lupus nephritis.","authors":"Rong Fu,Afroditi Boulougoura,Shuilian Yu,Hao Li,Wenliang Pan,Yushiro Endo,Rhea Bhargava,Abhiyan Satyam,Vivek Kasinath,Jarrat Jordan,Nandan Padmanabha,Maria G Tsokos,Reza Abdi,George C Tsokos","doi":"10.1002/art.43395","DOIUrl":null,"url":null,"abstract":"OBJECTIVE\r\nUpregulation of Interleukin 23 (IL-23) in the serum and kidneys of patients with lupus nephritis (LN) has been demonstrated, but its effect on podocytes remains unknown. We hypothesized that IL-23 contributes to podocyte injury and that targeted deletion of IL-23R in podocytes of lupus-prone mice can prevent the development of glomerulonephritis.\r\n\r\nMETHODS\r\nKidney biopsies were immunostained for IL-23R. In vitro experiments were conducted using a human podocyte cell line and primary murine podocytes. Human podocytes stimulated with IL-23 underwent bulk-RNA sequencing. The expression of IL-23R, structure and motility of podocytes were assessed. Podocytes isolated from B6 wild type mice injected with a minicircle (MC) encoding IL-23 were studied. To assess the role of IL-23R in the development of nephritis, we generated podocyte-specific Il23r deficient MRL/lpr lupus-prone mice.\r\n\r\nRESULTS\r\nIL-23R was highly expressed in the glomeruli of patients with LN. IL-23R expression was also upregulated in human podocytes and primary podocytes isolated from B6 mice after IL-23 stimulation. Human podocytes stimulated with IL-23 showed decreased expression of synaptopodin and remodeling of the actin cytoskeleton. IL-23 MC-administered mice exhibited a significant increase in the expression of IL-23R and phosphorylated STAT3 (pSTAT3) in podocytes. Finally, MRL/lpr.Podo-Cre+ Il23rfl/fl mice showed decreased clinical and histologic features of LN.\r\n\r\nCONCLUSION\r\nIL-23R expression is increased in podocytes from mice and humans with systemic lupus erythematosus. IL-23 signaling disrupts the cytoskeleton in podocytes and increases their mobility leading to the development of glomerulonephritis. Podocyte-specific deletion of Il23r in lupus-prone mice abrogates the development of LN.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"76 1","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/art.43395","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
OBJECTIVE
Upregulation of Interleukin 23 (IL-23) in the serum and kidneys of patients with lupus nephritis (LN) has been demonstrated, but its effect on podocytes remains unknown. We hypothesized that IL-23 contributes to podocyte injury and that targeted deletion of IL-23R in podocytes of lupus-prone mice can prevent the development of glomerulonephritis.
METHODS
Kidney biopsies were immunostained for IL-23R. In vitro experiments were conducted using a human podocyte cell line and primary murine podocytes. Human podocytes stimulated with IL-23 underwent bulk-RNA sequencing. The expression of IL-23R, structure and motility of podocytes were assessed. Podocytes isolated from B6 wild type mice injected with a minicircle (MC) encoding IL-23 were studied. To assess the role of IL-23R in the development of nephritis, we generated podocyte-specific Il23r deficient MRL/lpr lupus-prone mice.
RESULTS
IL-23R was highly expressed in the glomeruli of patients with LN. IL-23R expression was also upregulated in human podocytes and primary podocytes isolated from B6 mice after IL-23 stimulation. Human podocytes stimulated with IL-23 showed decreased expression of synaptopodin and remodeling of the actin cytoskeleton. IL-23 MC-administered mice exhibited a significant increase in the expression of IL-23R and phosphorylated STAT3 (pSTAT3) in podocytes. Finally, MRL/lpr.Podo-Cre+ Il23rfl/fl mice showed decreased clinical and histologic features of LN.
CONCLUSION
IL-23R expression is increased in podocytes from mice and humans with systemic lupus erythematosus. IL-23 signaling disrupts the cytoskeleton in podocytes and increases their mobility leading to the development of glomerulonephritis. Podocyte-specific deletion of Il23r in lupus-prone mice abrogates the development of LN.
期刊介绍:
Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.