Loss of SIRPα promotes podocytes presenting antigen to activate specific T cell immune responses in lupus nephritis via activating spleen tyrosine kinase
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ABSTRACT:
PROVIDER: PRJNA1005685 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the role of SIRPα in podocytes, we generated podocyte-specific SIRPα knockout mice, Subsequent studies have found that SIRPa is deeply involved in the adaptive immune process of podocytes, and the loss of SIRPa promotes the ability of podocytes to present antigens,furthermore, the loss of SIRPa in podocytes can promote the increase of antigen presentation ability of podocytes and promote the progression of lupus nephrin
2024-05-24 | GSE240916 | GEO
Project description:Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.
2024-06-10 | GSE263909 | GEO
Project description:Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. T cell from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). Here we evaluated the functional role of CaMKIV in lupus nephritis (LN) using kidney biopsy specimens and human podocyte cell line (AB8/13). We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. CaMKIV expression was found to be increased in podocytes of LN kidney biopsy specimens and exposure to IgG from LN patients. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkivM-bM-^HM-^R/M-bM-^HM-^R mice. IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. These findings may indicate that inhibition of CaMKIV may prove of clinical use in patients with LN. IgG Purification Kits (Dojindo Molecular Technologies, Inc.) are used for isolation and purification of immunoglobulin G of healthy and normal individual according to the manufacturerM-bM-^@M-^Ys protocol. Flow through the column was used for non IgG binding samples. Cultured human podocytes with IgG purified from sera of normal individuals and LN patient for 24 hr were collected for RNA.
2014-08-01 | E-GEOD-55768 | biostudies-arrayexpress
Project description:Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. T cell from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). Here we evaluated the functional role of CaMKIV in lupus nephritis (LN) using kidney biopsy specimens and human podocyte cell line (AB8/13). We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. CaMKIV expression was found to be increased in podocytes of LN kidney biopsy specimens and exposure to IgG from LN patients. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv−/− mice. IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. These findings may indicate that inhibition of CaMKIV may prove of clinical use in patients with LN.
2014-08-01 | GSE55768 | GEO
Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.
2012-12-01 | E-GEOD-42648 | biostudies-arrayexpress
Project description:Type-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the efficacy of SIRPα in regulating ILC2-mediated AHR, we utilized SIRPα and CD47 deficient mice in a murine model of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement with SIRPα reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type two cytokines. Additionally, our studies on human cells have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of a SIRPα agonist effectively suppresses the effector function and cytokine production of ILC2s. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviated AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.
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Project description:The goal of our study was to characterize glomerulus and particularly podocyte biology during MMF treatment in an immune-triggered proteinuric glomerulopathy. Therefore, nephrotoxic serum nephritis was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) (NTS+MMF) for one week, the other half of animals with vehicle (NTS+veh). A further group without induction and treatment served as controls (C). On day 10, we performed proteomic analysis of glomeruli.
2023-08-30 | PXD039915 | Pride
Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1.
2012-12-01 | GSE42648 | GEO
Project description:To compare the inflammatory responses of WT and SIRPα KO macrophage, we performed a complete transcript profiling of WT and SIRPα-KO M1 macrophage using transcriptome sequencing as a discovery platform. SIRPα-KO mice and WT mice were kept under the same condition. BMDMs were produced from WT and SIRPα-KO mice followed by M1 polarization. RNA was then isolated from the same number of BMDMs.
2021-03-19 | GSE169177 | GEO
Project description:Purpose: Next-generation sequencing (NGS) was used to define the transcriptome of native mouse podocytes and non-podocytes glomerular cells as part of a project aiming to define the molecular fingerprint of mouse podocytes. Method: Glomeruli from 29 Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J x hNPHS2Cre mice at the age of 10 weeks were purified and a single cell solution was prepared to seperate GFP-expressing (podocytes) and GFP-negative (non-podocytes glomerular cells) cells by FACS sorting. RNA was extracted and prepared for further analysis using directional, polyA+ library preparation. An Illumina HiSeq2500 was used for a paired-end sequencing of 100 cycles . Salmon and Sleuth were used for downstream analysis. Results: A total of 100 Million reads each from podocytes and non-podocytes glomerular cells could be used for further analysis.
2019-01-01 | E-MTAB-5457 | biostudies-arrayexpress