Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice

KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing...

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Autores principales:	Lisa Schmidtke, Myriam Meineck, Sabrina Saurin, Svenja Otten, Fabian Gather, Katharina Schrick, Rudolf Käfer, Wilfried Roth, Hartmut Kleinert, Julia Weinmann-Menke, Andrea Pautz
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	systemic lupus erythematosus glomerulonephritis post-transcriptional regulation cytokine KSRP Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/da5060350d0742d68f0b00959c48e6d9
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spelling	oai:doaj.org-article:da5060350d0742d68f0b00959c48e6d92021-11-25T17:12:15ZKnockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice10.3390/cells101131672073-4409https://doaj.org/article/da5060350d0742d68f0b00959c48e6d92021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3167https://doaj.org/toc/2073-4409KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing multiple organ manifestations; MRL-Fas<sup>lpr</sup> mice are an established mouse model to study lupus disease pathogenesis. To investigate the impact of KSRP on lupus disease progression, we generated KSRP-deficient MRL-Fas<sup>lpr</sup> mice (MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice). In line with the predicted role of KSRP as a negative regulator of cytokine expression, lupus nephritis was augmented in MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice. Increased infiltration of immune cells, especially of IFN-γ producing T cells and macrophages, driven by enhanced expression of T cell-attracting chemokines and adhesion molecules, seems to be responsible for worsened kidney morphology. Reduced expression of the anti-inflammatory interleukin-1 receptor antagonist may be another reason for severe inflammation. The increase of FoxP3<sup>+</sup> T cells detected in the kidney seems unable to dampen the massive kidney inflammation. Interestingly, lymphadenopathy was reduced in MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice. Altogether, KSRP appears to have a complex role in immune regulation; however, it is clearly able to ameliorate lupus nephritis.Lisa SchmidtkeMyriam MeineckSabrina SaurinSvenja OttenFabian GatherKatharina SchrickRudolf KäferWilfried RothHartmut KleinertJulia Weinmann-MenkeAndrea PautzMDPI AGarticlesystemic lupus erythematosusglomerulonephritispost-transcriptional regulationcytokineKSRPBiology (General)QH301-705.5ENCells, Vol 10, Iss 3167, p 3167 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	systemic lupus erythematosus glomerulonephritis post-transcriptional regulation cytokine KSRP Biology (General) QH301-705.5
spellingShingle	systemic lupus erythematosus glomerulonephritis post-transcriptional regulation cytokine KSRP Biology (General) QH301-705.5 Lisa Schmidtke Myriam Meineck Sabrina Saurin Svenja Otten Fabian Gather Katharina Schrick Rudolf Käfer Wilfried Roth Hartmut Kleinert Julia Weinmann-Menke Andrea Pautz Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
description	KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing multiple organ manifestations; MRL-Fas<sup>lpr</sup> mice are an established mouse model to study lupus disease pathogenesis. To investigate the impact of KSRP on lupus disease progression, we generated KSRP-deficient MRL-Fas<sup>lpr</sup> mice (MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice). In line with the predicted role of KSRP as a negative regulator of cytokine expression, lupus nephritis was augmented in MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice. Increased infiltration of immune cells, especially of IFN-γ producing T cells and macrophages, driven by enhanced expression of T cell-attracting chemokines and adhesion molecules, seems to be responsible for worsened kidney morphology. Reduced expression of the anti-inflammatory interleukin-1 receptor antagonist may be another reason for severe inflammation. The increase of FoxP3<sup>+</sup> T cells detected in the kidney seems unable to dampen the massive kidney inflammation. Interestingly, lymphadenopathy was reduced in MRL-Fas<sup>lpr</sup>/KSRP<sup>−/−</sup> mice. Altogether, KSRP appears to have a complex role in immune regulation; however, it is clearly able to ameliorate lupus nephritis.
format	article
author	Lisa Schmidtke Myriam Meineck Sabrina Saurin Svenja Otten Fabian Gather Katharina Schrick Rudolf Käfer Wilfried Roth Hartmut Kleinert Julia Weinmann-Menke Andrea Pautz
author_facet	Lisa Schmidtke Myriam Meineck Sabrina Saurin Svenja Otten Fabian Gather Katharina Schrick Rudolf Käfer Wilfried Roth Hartmut Kleinert Julia Weinmann-Menke Andrea Pautz
author_sort	Lisa Schmidtke
title	Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
title_short	Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
title_full	Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
title_fullStr	Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
title_full_unstemmed	Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice
title_sort	knockout of the kh-type splicing regulatory protein drives glomerulonephritis in mrl-fas<sup>lpr</sup> mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/da5060350d0742d68f0b00959c48e6d9
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Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> Mice

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