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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MDPI AG
2021-11-01
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:36:49Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T05:36:49Z |
| publishDate | 2021-11-01 |
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| series | Cells |
| spelling | doaj.art-da5060350d0742d68f0b00959c48e6d92023-11-22T22:52:16ZengMDPI AGCells2073-44092021-11-011011316710.3390/cells10113167Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Fas<sup>lpr</sup> MiceLisa Schmidtke0Myriam Meineck1Sabrina Saurin2Svenja Otten3Fabian Gather4Katharina Schrick5Rudolf Käfer6Wilfried Roth7Hartmut Kleinert8Julia Weinmann-Menke9Andrea Pautz10Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyFirst Medical Department, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyFirst Medical Department, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyKH-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.https://www.mdpi.com/2073-4409/10/11/3167systemic lupus erythematosusglomerulonephritispost-transcriptional regulationcytokineKSRP |
| spellingShingle | 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 Cells systemic lupus erythematosus glomerulonephritis post-transcriptional regulation cytokine KSRP |
| title | 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_short | 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 |
| topic | systemic lupus erythematosus glomerulonephritis post-transcriptional regulation cytokine KSRP |
| url | https://www.mdpi.com/2073-4409/10/11/3167 |
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