Interleukin-23 receptor deficiency in podocytes averts the development of lupus nephritis.

IF 10.9 1区 医学 Q1 RHEUMATOLOGY
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
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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.
足细胞中白细胞介素-23受体缺乏可避免狼疮肾炎的发展。
目的已证实狼疮肾炎(LN)患者血清和肾脏中白细胞介素23 (IL-23)的上调,但其对足细胞的影响尚不清楚。我们假设IL-23有助于足细胞损伤,并且靶向删除狼疮易感小鼠足细胞中的IL-23R可以预防肾小球肾炎的发展。方法肾活检组织进行IL-23R免疫染色。用人足细胞细胞系和小鼠原代足细胞进行体外实验。用IL-23刺激人足细胞进行大体积rna测序。观察IL-23R的表达、足细胞的结构和活力。对B6野生型小鼠足细胞注射编码IL-23的微环(MC)进行了研究。为了评估IL-23R在肾炎发展中的作用,我们制造了足细胞特异性IL-23R缺陷MRL/lpr狼疮易感小鼠。结果sil - 23r在LN患者肾小球中高表达。IL-23刺激后,人足细胞和B6小鼠原代足细胞中IL-23R的表达也上调。IL-23刺激的人足细胞显示突触蛋白表达减少和肌动蛋白细胞骨架重塑。IL-23 mc组小鼠足细胞中IL-23R和磷酸化STAT3 (pSTAT3)的表达显著增加。最后,推广/ lpr。Podo-Cre+ Il23rfl/fl小鼠LN的临床和组织学特征降低。结论il - 23r在小鼠和人系统性红斑狼疮足细胞中表达升高。IL-23信号破坏足细胞的细胞骨架,增加其流动性,导致肾小球肾炎的发展。在狼疮易感小鼠中,足细胞特异性缺失Il23r可消除狼疮的发生。
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来源期刊
Arthritis & Rheumatology
Arthritis & Rheumatology RHEUMATOLOGY-
CiteScore
20.90
自引率
3.00%
发文量
371
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.
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