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.
authors.affiliation: Molecular Pathology Research Group, Faculty of Medicine, University of Tromsø, Tromsø, Norway.
authors.forename: Dhivya
authors.initials: D
authors.lastname: Thiyagarajan
authors.forename: Silje
authors.initials: S
authors.lastname: Fismen
authors.forename: Natalya
authors.initials: N
authors.lastname: Seredkina
authors.forename: Søren
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Elung-Jensen
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Kamper
authors.forename: Christopher Graham
authors.initials: CG
authors.lastname: Fenton
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Rekvig
authors.forename: Elin Synnøve
authors.initials: ES
authors.lastname: Mortensen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000201:enzymology*; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D008181:Lupus Nephritis / Q000201:enzymology / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C482593:CLEC4D protein, human; D002843:Chromatin; C113583:Clecsf8 protein, mouse; D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D003850:Deoxyribonuclease I