Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Harvard

APA

CBE

MLA

Vancouver

Author

Thiyagarajan, Dhivya ; Fismen, Silje ; Seredkina, Natalya ; Jacobsen, Søren ; Elung-Jensen, Thomas ; Kamper, Anne-Lise ; Fenton, Christopher Graham ; Rekvig, Ole Petter ; Mortensen, Elin Synnøve. / Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e. I: P L o S One. 2012 ; Bind 7, Nr. 3. s. e34080.

Bibtex

@article{60296f6551c842e4aa29c4c65cd0ad7f,
title = "Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e",
abstract = "Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7-9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease.",
keywords = "Animals, Cells, Cultured, Chromatin, Cytokines, Deoxyribonuclease I, Disease Models, Animal, Female, Gene Silencing, Humans, Inflammation, Kidney, Lectins, C-Type, Lupus Nephritis, Membrane Proteins, Mice, Principal Component Analysis, RNA, Messenger, Receptors, Immunologic, Signal Transduction, Toll-Like Receptors",
author = "Dhivya Thiyagarajan and Silje Fismen and Natalya Seredkina and S{\o}ren Jacobsen and Thomas Elung-Jensen and Anne-Lise Kamper and Fenton, {Christopher Graham} and Rekvig, {Ole Petter} and Mortensen, {Elin Synn{\o}ve}",
year = "2012",
doi = "10.1371/journal.pone.0034080",
language = "English",
volume = "7",
pages = "e34080",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

RIS

TY - JOUR

T1 - Silencing of renal DNaseI in murine lupus nephritis imposes exposure of large chromatin fragments and activation of Toll like receptors and the Clec4e

AU - Thiyagarajan, Dhivya

AU - Fismen, Silje

AU - Seredkina, Natalya

AU - Jacobsen, Søren

AU - Elung-Jensen, Thomas

AU - Kamper, Anne-Lise

AU - Fenton, Christopher Graham

AU - Rekvig, Ole Petter

AU - Mortensen, Elin Synnøve

PY - 2012

Y1 - 2012

N2 - Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7-9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease.

AB - Recent studies demonstrate that transformation of mild lupus nephritis into end-stage disease is imposed by silencing of renal DNaseI gene expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation, and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals that produce IgG anti-chromatin antibodies. The main focus of the present study is to describe the biological consequences of renal DNaseI shut-down and reduced chromatin fragmentation with a particular focus on whether exposed large chromatin fragments activate Toll like receptors and the necrosis-related Clec4e receptor in murine and human lupus nephritis. Furthermore, analyses where performed to determine if matrix metalloproteases are up-regulated as a consequence of chromatin-mediated Toll like receptors/Clec4e stimulation. Mouse and human mRNA expression levels of DNaseI, Toll like receptors 7-9, Clec4e, pro-inflammatory cytokines and MMP2/MMP9 were determined and compared with in situ protein expression profiles and clinical data. We demonstrate that exposure of chromatin significantly up-regulate Toll like receptors and Clec4e in mice, and also but less pronounced in patients with lupus nephritis treated with immunosuppresants. In conclusion, silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals leading to progression of both murine and human lupus nephritis. Principal component analyses biplot of data from murine and human lupus nephrits demonstrate the importance of DNaseI gene shut down for progression of the organ disease.

KW - Animals

KW - Cells, Cultured

KW - Chromatin

KW - Cytokines

KW - Deoxyribonuclease I

KW - Disease Models, Animal

KW - Female

KW - Gene Silencing

KW - Humans

KW - Inflammation

KW - Kidney

KW - Lectins, C-Type

KW - Lupus Nephritis

KW - Membrane Proteins

KW - Mice

KW - Principal Component Analysis

KW - RNA, Messenger

KW - Receptors, Immunologic

KW - Signal Transduction

KW - Toll-Like Receptors

U2 - 10.1371/journal.pone.0034080

DO - 10.1371/journal.pone.0034080

M3 - Journal article

VL - 7

SP - e34080

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 3

ER -

ID: 36584026