miR-21 regulation of autoreactive B cell and lupus nephritis development

miR-21对自身反应性B细胞和狼疮性肾炎发展的调节

• 批准号: 10888833
• 负责人: Ziaur Rahman
• 金额: $ 54.37万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-18 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10888833
• 关键词: Affect; American; Antibodies; Asthma; Attenuated; Autoantibodies; Autoimmune; Autoimmune Responses; Autoimmunity; Automobile Driving; B-Cell Activation; B-Lymphocytes; Binding Sites; Bone Marrow; Cells; Cellular Metabolic Process; Cre lox recombination system; Data; Development; Disease; Disease Progression; Exhibits; Experimental Autoimmune Encephalomyelitis; FRAP1 gene; Gene Expression; Genes; Grant; Helper-Inducer T-Lymphocyte; Human; Immune; Immunity; Inflammatory; Interferon Type I; Knowledge; Learning; Ligands; Lupus Nephritis; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; MicroRNAs; Modeling; Mus; NF-kappa B; Oligonucleotides; Onset of illness; Oxygen Consumption; PIK3CG gene; Pathway interactions; Patients; Persons; Phenotype; Plasma Cells; Production; Promoter Regions; Regulation; Regulator Genes; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; TLR7 gene; Tamoxifen; Testing; autoreactive B cell; comparison control; extracellular; human model; inducible Cre; mouse model; mutant; overexpression; posttranscriptional; response; systemic autoimmunity; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing

Project Summary MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression in immunity and autoimmunity, although many miRNAs remain poorly characterized. One such miRNA, miRNA-21 (miR-21), is upregulated in systemic lupus erythematosus (SLE) patients and promotes various diseases in mouse models. These include experimental autoimmune encephalomyelitis (EAE), asthma, cancer, and our findings on its role in toll-like receptor 7 (TLR7)-driven SLE in mice. We found that TLR7 overexpressing SLE-prone B6.Sle1bYaa mice deficient in miR-21 (Sle1bYaamiR-21-/-) had reduced germinal center (GC) B cell, T follicular helper (Tfh) cell and plasma cell (PC) responses. These responses in Sle1bYaamiR-21-/- mice were strongly associated with reduced autoantibody, and splenic and bone marrow autoantibody-producing antibody forming cell (AFC) responses. These data substantiate a role for miR-21 in the loss of B cell tolerance and autoimmunity, which necessitates identification of mechanisms (focus of the grant) by which miR-21 promotes autoantibody production and SLE. This will fill gaps in knowledge and may help discover an urgently needed targeted therapy for SLE, a debilitating disease that affects millions of Americans and people world-wide. TLR signaling, especially TLR7, promotes SLE in humans and murine models, and an attractive therapeutic target. TLR7 signaling activates the NF-kB inflammatory signaling pathway. TLR7 upregulates miR-21 expression in B cells which can target the negative regulator of NF-kB signaling, Peli1, although the role of miR-21 in regulating NF- kB signaling in SLE-prone B cells by targeting Peli1 is unknown. Preliminary data showed that B cells from Sle1bYaamiR-21-/- mice have increased Peli1 expression compared to control Sle1bYaa B cells. In addition, previous studies implicated TLR signaling in metabolic reprogramming, primarily through the activation of the PI3K/Akt/mTOR pathway in various immune conditions, although the role of this pathway in TLR7-mediated metabolic reprograming in B cells in SLE is not clear. miR-21 was also shown to regulate the PI3K/Akt/mTOR pathway in various models; however, its role in regulating B cell metabolism in TLR7-driven SLE is not known. Interestingly, our RNA-seq analysis of B cells from a TLR7-induced model showed negatively enriched genes in the PI3K/Akt/mTOR pathway in the absence of miR-21. Additional preliminary data showed increased extracellular acidification (ECAR) and oxygen consumption (OCR) rates in Sle1bYaa B cells overexpressing TLR7 compared to Sle1b B cells, indicating a more energetic phenotype in response to TLR7 signaling. Conversely, Sle1bYaamiR-21-/- B cells exhibited reduced ECAR and OCR compared to Sle1bYaa B cells. We hypothesize that miR-21 promotes TLR7-driven systemic autoimmune responses and SLE disease by regulating TLR7-NF-kB signaling and metabolic reprogramming in B cells. Proposed hypothesis and specific aims will help delineate the mechanism by which miR-21 drives autoimmune responses and lupus nephritis and will inform us whether miR-21 or miR-21 regulated pathway(s) can be a therapeutic target for SLE.

项目概要 MicroRNA (miRNA) 是免疫和免疫中基因表达的关键转录后调节因子 自身免疫，尽管许多 miRNA 的特征仍不清楚。其中一种 miRNA，miRNA-21 (miR-21)，是 在系统性红斑狼疮 (SLE) 患者中表达上调，并在小鼠模型中促进多种疾病。 其中包括实验性自身免疫性脑脊髓炎 (EAE)、哮喘、癌症以及我们对其作用的发现 小鼠中 Toll 样受体 7 (TLR7) 驱动的 SLE。我们发现 TLR7 过度表达易患 SLE 的 B6.Sle1bYaa miR-21 缺陷的小鼠 (Sle1bYaamiR-21-/-) 生发中心 (GC) B 细胞和滤泡辅助 T (Tfh) 减少 细胞和浆细胞（PC）反应。 Sle1bYaamiR-21-/- 小鼠的这些反应与 自身抗体减少，以及脾和骨髓产生自身抗体的抗体形成细胞（AFC） 回应。这些数据证实了 miR-21 在 B 细胞耐受性和自身免疫性丧失中的作用，这 需要确定 miR-21 促进自身抗体的机制（资助的重点） 生产和 SLE。这将填补知识空白，并可能有助于发现迫切需要的目标 SLE 是一种使人衰弱的疾病，影响着数百万美国人和世界各地的人们。 TLR 信号传导， 尤其是 TLR7，在人类和小鼠模型中促进 SLE，并且是一个有吸引力的治疗靶点。 TLR7 信号传导激活 NF-kB 炎症信号通路。 TLR7 上调 B 细胞中 miR-21 的表达 它可以靶向 NF-kB 信号转导的负调节因子 Peli1，尽管 miR-21 在调节 NF- 尚不清楚易患 SLE 的 B 细胞中通过靶向 Peli1 的 kB 信号传导。初步数据显示，B 细胞来自 与对照 Sle1bYaa B 细胞相比，Sle1bYaamiR-21-/- 小鼠 Peli1 表达增加。此外， 之前的研究表明 TLR 信号传导参与代谢重编程，主要是通过激活 PI3K/Akt/mTOR 通路在各种免疫条件下的作用，尽管该通路在 TLR7 介导中的作用 SLE 中 B 细胞的代谢重编程尚不清楚。 miR-21 还被证明可以调节 PI3K/Akt/mTOR 各种模型中的路径；然而，其在 TLR7 驱动的 SLE 中调节 B 细胞代谢的作用尚不清楚。 有趣的是，我们对 TLR7 诱导模型中的 B 细胞进行 RNA-seq 分析，结果显示基因负富集 在没有 miR-21 的情况下，PI3K/Akt/mTOR 通路中的额外的初步数据显示增加 Sle1bYaa B 细胞过表达的细胞外酸化 (ECAR) 和耗氧 (OCR) 率 TLR7 与 Sle1b B 细胞相比，表明响应 TLR7 信号传导的能量更高的表型。 相反，与 Sle1bYaa B 细胞相比，Sle1bYaamiR-21-/- B 细胞表现出 ECAR 和 OCR 降低。我们 假设 miR-21 通过 TLR7 驱动的系统性自身免疫反应和 SLE 疾病促进 调节 B 细胞中的 TLR7-NF-kB 信号传导和代谢重编程。提出的假设和具体 目标将有助于阐明 miR-21 驱动自身免疫反应和狼疮肾炎的机制 并将告诉我们 miR-21 或 miR-21 调节的通路是否可以成为 SLE 的治疗靶点。