FRI0216B SELECTIVE IRAK4 INHIBITOR DAMPENS MYD88 SIGNALING AND AMELIORATES INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF LUPUS NEPHRITIS

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

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Blocking glomerular immunoglobulin deposits in a mouse model of lupus nephritis on indirect immunofluorescence with the use of Fab fragments

Journal of Immunological Methods ◽

10.1016/j.jim.2011.11.008 ◽

2012 ◽

Vol 376 (1-2) ◽

pp. 139-142

Author(s):

Ioannis Petrakis ◽

Vasiliki Mavroeidi ◽

Kostas Stylianou ◽

Konstantinos Giannakakis ◽

Eugene Daphnis

Keyword(s):

Lupus Nephritis ◽

Mouse Model ◽

Indirect Immunofluorescence ◽

Fab Fragments ◽

Immunoglobulin Deposits

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Low-Molecular-Weight Heparin Enhanced Therapeutic Effects of Human Adipose-Derived Stem Cell Administration in a Mouse Model of Lupus Nephritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.792739 ◽

2022 ◽

Vol 12 ◽

Author(s):

Shogo Matsuda ◽

Takuya Kotani ◽

Takashi Saito ◽

Takayasu Suzuka ◽

Tatsuhiko Mori ◽

...

Keyword(s):

Gene Expression ◽

Molecular Weight ◽

Lupus Nephritis ◽

Mouse Model ◽

Therapeutic Effect ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight ◽

Cellular Functions ◽

Igg Antibody ◽

Gene Expression Levels

BackgroundLupus nephritis is a life-threatening complication in systemic lupus erythematosus (SLE), but the efficiency of current therapies involving corticosteroids, immunosuppressants, and biological agents is limited. Adipose-derived mesenchymal stem cells (ASCs) are gaining attention as a novel treatment for inflammation in SLE. Low-molecular-weight heparin (LMWH) exhibits multiple functions including anti-inflammatory, anti-fibrotic, and cell function-promoting effects. LMWH stimulation is expected to increase the therapeutic effect of ASCs by promoting cellular functions. In this study, we investigated the effects of LMWH on ASC functions and the therapeutic effect of LMWH-activated human-ASCs (hep-hASCs) in an SLE mouse model.MethodsThe cellular functions of human-derived ASCs stimulated with different LMWH concentrations were observed, and the optimum LMWH dose was selected. The mice were assigned to control, human-ASC, and hep-hASC groups; treatments were performed on week 20. Twenty-six week-old mice were sacrificed, and urine protein score, serum blood urea nitrogen, creatinine (Cr), anti-ds DNA IgG antibody, and serum IL-6 levels were analyzed in each group. Mice kidneys were evaluated via histological examination, immunohistochemical staining, and gene expression levels.ResultsLMWH significantly promoted ASC migration and proliferation and hepatocyte growth factor production and upregulated immunomodulatory factors in vitro. Hep-hASC administration resulted in significant disease activity improvement including proteinuria, serum Cr and IL-6 levels, anti-ds DNA IgG antibody, glomerulonephritis, and immune complex in mice. Inflammation and fibrosis in kidneys was significantly suppressed in the hep-hASC group; the gene expression levels of TNF-alpha, TIMP-2, and MMP-2 was significantly downregulated in the hep-hASC group compared with the control group.ConclusionsHep-hASC exhibited higher anti-inflammatory and anti-fibrotic effects than hASCs and may be a candidate tool for SLE treatment in future.

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