Knockout of the KH-Type Splicing Regulatory Protein Drives Glomerulonephritis in MRL-Faslpr Mice.

Lisa Schmidtke,Katharina Schrick,Sabrina Saurin,Andrea Pautz,Fabian Gather,Myriam Meineck,Hartmut Kleinert,Julia Weinmann-Menke,Wilfried Roth,Rudolf Käfer,Svenja Otten

doi:10.3390/cells10113167

Abstract

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-Faslpr 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-Faslpr mice (MRL-Faslpr/KSRP−/− mice). In line with the predicted role of KSRP as a negative regulator of cytokine expression, lupus nephritis was augmented in MRL-Faslpr/KSRP−/− 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+ T cells detected in the kidney seems unable to dampen the massive kidney inflammation. Interestingly, lymphadenopathy was reduced in MRL-Faslpr/KSRP−/− mice. Altogether, KSRP appears to have a complex role in immune regulation; however, it is clearly able to ameliorate lupus nephritis.

Highlights

In the 10th generation, we started to analyze the phenotype of MRL-Faslpr KH-type splicing regulatory protein (KSRP)−/− mice compared to MRL-Faslpr wild-type mice (MRL-Faslpr KSRP+/+ )
The autoimmune symptoms in MRL-Faslpr mice develop gradually and become visible at the age of 3 months until they become severe at about 5 months
The knockout of the KSRP protein (Figure S1) enhanced glomerulonephritis severity in the kidneys of female and male MRL-Faslpr KSRP−/− mice at 19 weeks of age. Both in interstitial tissue as well as the glomeruli, we detected worsened kidney morphology via the evaluation of glomerular lesions, tubular damage, and the increased numbers of infiltrating cells in MRL-Faslpr KSRP−/− compared to MRL-Faslpr KSRP+/+ mice, indicating more severe glomerulonephritis in MRL-Faslpr KSRP−/− mice

Summary

Introduction

Depending on the origin and location of the immune complex deposition, patients experience various organ manifestations (e.g., vasculitis, glomerulonephritis, arthritis, skin manifestations, etc.). Both the cells and structures of the non-specific immune defense (plasmacytoid and myeloid dendritic cells, macrophages, neutrophil granulocytes, toll-like receptors and complement system), as well as the specific immune defense (T and B cells), interact in the pathogenesis of SLE [1,2,3]. Despite the recent advances in SLE therapy, a number of patients fail to respond, respond inadequately to the potent anti-inflammatory and immunosuppressive therapies, or have severe adverse effects [5,6]

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Results

Conclusion