Inactivation of the KSRP gene modifies collagen antibody induced arthritis. (July 2017)

• Record Type: Journal Article
• Authors: Käfer, Rudolf; Schrick, Katharina; Schmidtke, Lisa; Montermann, Evelyn; Hobernik, Dominika; Bros, Matthias; Chen, Ching-Yi; Kleinert, Hartmut; Pautz, Andrea
• Is Part Of: Molecular immunology. Volume 87(2017:Jul.)
• Page Start: 207
• Page End: 216
• Publication Date: 2017-07
• Subjects: 3′-UTR 3′-untranslated region -- AI arthritis index -- ARE AU-rich element -- ARE-BP ARE binding protein -- CAIA collagen antibody induced arthritis -- CBA cytometric bead array -- CIA collagen induced arthritis -- CII collagen type II -- FACS fluorescent activated cell sorting -- KSRP KH-type splicing regulatory protein -- iNOS inducible NO synthase -- mAB monoclonal antibody -- PBMC peripheral blood monocytes -- qRT-PCR quantitative real time reverse transcription polymerase chain reaction -- RA rheumatoid arthritis -- RBP RNA-binding protein -- Pol2A RNA polymerase II; Rheumatoid arthritis -- CAIA -- KSRP -- Pro-inflammatory mediators -- Gene expression; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2017.05.003
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: In cell culture and primary cells KSRP is a negative regulator of pro-inflammatory gene expression. Surprisingly, KSRP −/− -mice are less susceptible to CAIA induction. KSRP −/− -mice display decreased expression of pro-inflammatory cytokines in joints. KSRP −/− -mice showed less infiltration of immune cells to the inflamed joint. The decreased number of myeloid cells in KSRP −/− -mice may account for this effect. Abstract: The KH type splicing regulatory protein (KSRP) is a nucleic acid binding protein, which negatively regulates the stability and/or translatability of many mRNA species encoding immune-relevant proteins. As KSRP is expressed in immune cells including T and B cells, neutrophils, macrophages and dendritic cells, we wanted to analyze its importance for the development of autoimmune diseases. We chose collagen antibody-induced arthritis (CAIA) as an appropriate autoimmune disease mouse model in which neutrophils and macrophages constitute the main effector cell populations. We compared arthritis induction in wild type (WT) and KSRP −/− mice and paws were taken for histological sections and qPCR analysis. Furthermore, we determined the frequencies of spleen immune cells by flow cytometry. Cytokine levels in spleen cell supernatants were determined by cytometric bead array analyses (CBA). After CAIA induction we unexpectedly observed in WT animals much stronger swelling of the paws than in KSRP −/− mice. In accordance, histological staining of paw sections of KSRP −/− animals revealed much lower frequencies of infiltrating immune cells in the joints compared to WT animals. Furthermore, CAIA-treatment resulted in reduced expression of several inflammatory factors (like CXCL-1, iNOS, TNF-α and S100A8) as well as immune cell marker genes (e.g. LFA-1, CD68, Ly6G) in the joints of KSRP −/− mice. Spleen cells of KSRP −/− mice showed lower frequencies of myeloid cells. On cytokine level IFN-γ production was increased in spleen cells of KSRP −/− mice compared to WT samples. These data surprisingly suggest that the absence of KSRP protects against the induction of inflammatory arthritis.