Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Donadio, Maria Elena; Loiacono, Elisa; Peruzzi, Licia; Amore, Alessandro; Camilla, Roberta; Chiale, Federica; Vergano, Luca; Boido, Alberto; Conrieri, Margherita; Bianciotto, Manuela; Bosetti, Francesca; Coppo, Rosanna

doi:10.1007/s00467-014-2807-6

Cited by 63 publications

(52 citation statements)

References 31 publications

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“…In diabetic nephropathy, TLR4 activation promoted inflammation, podocyte and tubular epithelial cell injury, and interstitial fibrosis, having a great impact on the occurrence and development of this disorder (Ma et al., ). The expression of mRNAs encoding TLR4 was increased in IgA nephropathy, which presented with immune deposits of IgA within glomeruli (Donadio et al., ). Subsequently, TLR4 was claimed to be associated with membranous nephropathy, which is considered a non‐inflammatory organ‐specific autoimmune disease (Chen et al., ).…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of the long non‐coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR‐217–TLR4 pathway

Jin

Pan

et al. 2018

Experimental Physiology

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New Findings What is the central question of this study?What is the role of the long non‐coding RNA X‐inactive specific transcript (XIST), which is up‐regulated in injured podocytes and membranous nephropathy, in the pathogenesis of membranous nephropathy? What is the main finding and its importance?XIST was up‐regulated in kidney tissue with membranous nephropathy and in injured podocytes. Down‐regulation of XIST inhibited podocyte apoptosis. XIST negatively regulated miR‐217, and miR‐217 modulated Toll‐like receptor 4. Inhibition of XIST suppressed podocyte apoptosis induced by angiotensin II via miR‐217. Abstract Membranous nephropathy is often characterized by glomerular podocyte injury. Up‐regulation of the long non‐coding RNA (lncRNA) X‐inactive specific transcript (XIST) has been verified in membranous nephropathy and in injured podocytes. Here the role of XIST in podocyte injury and membranous nephropathy was explored. Quantitative real‐time PCR and western blot were performed to detect the expression of XIST and miR‐217, and Toll‐like receptor 4 (TLR4) protein, respectively. Podocyte apoptosis was evaluated with flow cytometry. Interaction between XIST and miR‐217 was analysed by RNA immunoprecipitation and RNA pull‐down assay. A dual luciferase reporter assay was used to examine the interplay between miR‐217 and TLR4. Up‐regulation of the lncRNA XIST and angiotensin II (Ang II) and kidney and podocyte injury were indicated in kidney tissue of patients with membranous nephropathy. Increase of XIST and apoptosis were induced by Ang II in podocytes. Down‐regulation of XIST reversed podocyte apoptosis induced by Ang II. MiR‐217 was negatively regulated by XIST. MiR‐217 controlled TLR4 by targeting its 3′‐untranslated region. XIST modulated TLR4 through miR‐217 and inhibition of XIST reduced podocyte apoptosis induced by Ang II via regulating miR‐217. Down‐regulation of XIST ameliorates podocyte apoptosis via the miR‐217–TLR4 pathway, which may improve membranous nephropathy.

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Section: Discussionmentioning

confidence: 99%

Down‐regulation of the long non‐coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR‐217–TLR4 pathway

Jin

Pan

et al. 2018

Experimental Physiology

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“…Increased immunoproteasome activity in APC results in upregulation of the activated form of NF‐κB, an anti‐apoptotic and pro‐inflammatory regulator of cytokine expression. There is also an emerging evidence for a role of increased immunoproteasome activity in IgAN . Excessive switching from proteasome to immunoproteasome in peripheral blood mononuclear cells has been observed in patients with IgAN with high levels of proteinuria .…”

Section: Bortezomib In Igan ( Clinicaltrialsgov Identifier: Nct01103mentioning

confidence: 99%

“…There is also an emerging evidence for a role of increased immunoproteasome activity in IgAN. 56 Excessive switching from proteasome to immunoproteasome in peripheral blood mononuclear cells has been observed in patients with IgAN with high levels of proteinuria. 57 The trigger for this switch is not clear, but it has been postulated that an aberrant response to mucosal immune challenge, such as to viral infections that trigger IFN gamma release, may be involved.…”

Section: Bortezomib In Igan (Clinicaltrialsgov Identifier: Nct011037mentioning

confidence: 99%

Emerging therapies in immunoglobulin A nephropathy

2015

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examines a number of current and recently commenced studies in immunoglobulin A nephropathy, emphasizing newer therapies and therapeutic targets. ABSTRACT:Despite advances in our understanding of immunoglobulin A nephropathy (IgAN) over the past decade, there are currently no specific therapies capable of targeting key pathways involved in the pathogenesis of the disease. Recent studies have, however, provided new insights into important molecular pathways that are likely to be amenable to therapeutic manipulation in the future. Specifically, a deeper understanding of the role of mucosal immunity, B-cell activation and mesangial cell activation in IgAN has provided the impetus for a number of exciting phase II/III clinical trials in IgAN. In this review, we examine some of these on-going studies, first examining studies that clarify the role of traditional immunosuppression in IgAN, then focusing on novel therapies in early clinical studies, looking closely at the rationale for these agents in relation to our current understanding of the pathogenesis of IgAN. Finally, we examine emerging pathways and therapeutic agents that have the potential to be developed as novel therapies in the coming years. It is hoped that as we continue to develop a greater understanding of IgAN, emerging therapies will soon become a reality in the day-to-day treatment of patients with IgAN.

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“…No clear regulatory mechanism has been identified to explain the abnormal immune function observed in patients with allergic purpura. Previous studies indicate that cellular immune dysfunction, manifesting as a Th1/Th2 imbalance in the acute phase and dominant activation of Th2 cells, is present in a significant proportion of pediatric patients with HSP (12)(13)(14)(15). Furthermore, Th17 cells are activated abnormally in these patients, and regulatory T (Treg) cells are reduced in number or exhibit reduced activity.…”

Section: Discussionmentioning

confidence: 99%

“…T helper (Th) cells, including Th1, Th2 and Th17, are involved in the pathogenesis of various types of vascular inflammation (9)(10)(11). Th cell subset functional imbalance and aberrant activation of Th2 and Th17 cells have been observed in patients with HSP (12)(13)(14)(15). However, the association between the TLR signaling pathways and Th1, Th2 and Th17 in the immune pathogenesis of HSP remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Association between toll-like receptor 6 expression and auxiliary T cells in the peripheral blood of pediatric patients with allergic purpura

Chang¹,

Cao²,

Lin³

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the correlations between toll-like receptor 6 (TLR6) expression in the peripheral blood mononuclear cells (PBMCs) and auxiliary T cells of children with purpura. A total of 42 children with acute Henoch-Schönlein purpura (HSP) were selected for the study, and a further 30 healthy children were selected as a control group. Enzyme-linked immunosorbent assays were performed to detect the levels of plasma interferon (IFN)-γ, interleukin (IL)-4 and IL-17, and flow cytometry was performed to detect the TLR6 protein expression levels in PBMCs. The plasma levels of IL-4, IFN-γ and IL-17 in the HSP group were significantly higher compared with those in the normal control group. TLR6 protein expression was significantly increased in the PBMCs of the HSP patients. The TLR6 protein expression levels in the monocytes of the HSP group significantly positively correlated with the serum IL-4 and IL-17 levels, but not with the serum levels of IFN-γ. Therefore, the results of the present study suggest that the activation of TLR6 may be involved in the immunopathogenesis of HSP, and that the activated TLR6 may mediate this process by upregulating the immune responses of type 2 T helper (Th2) and Th17 cells.

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Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy

Cited by 63 publications

References 31 publications

Down‐regulation of the long non‐coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR‐217–TLR4 pathway

Down‐regulation of the long non‐coding RNA XIST ameliorates podocyte apoptosis in membranous nephropathy via the miR‐217–TLR4 pathway

Emerging therapies in immunoglobulin A nephropathy

Association between toll-like receptor 6 expression and auxiliary T cells in the peripheral blood of pediatric patients with allergic purpura

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