Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice

Abstract

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.

Neutrophils Contribute to ER Stress in Lung Epithelial Cells in the Pristane-Induced Diffuse Alveolar Hemorrhage Mouse Model

“…ER stress is also known to drive hepatic, endothelial and epithelial cell apoptosis via reactive oxygen-dependent pathways and contribute to disease pathology in various models (39)(40)(41). Because IRE1-a activity has been shown in several models to be critical in regulating pristane-induced autoimmunity as well as pulmonary disease (21)(22)(23)(24)(25), we focused on sXbp1 driven ER stress in the lung after pristane administration and in keeping with previous studies we found that IRE1-a-dependent pathways to be involved. However, it should be noted that we did not fully explore ATF4 and ATF6 in this study and that a potential role for these pathways cannot be ruled out.…”

“…Inhibition of IRE1-a activity during pristane administration abolishes lupus nephritis, autoantibody levels, and cytokine production. Additionally, in the bleomycin pulmonary fibrosis model, IRE1-a inhibition reduces alveolar epithelial apoptosis and prevented fibrosis (24,25). Recently, crosstalk between NETs and ER stress has been observed in a model of sepsisinduced intestinal injury, with inhibition of NETosis and ER stress reducing intestinal epithelial cell monolayer barrier disruption, suggesting that neutrophils and NETosis contribute to ER stress in intestinal epithelial cells (26).…”

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases

“…IRE-1 is a central regulator of B cell differentiation [ 54 , 55 , 56 , 57 ], and B cell hyperactivity is a defining pathogenic event in SLE [ 3 , 58 ], with B cell depletion therapies being considered for the treatment of the disorder [ 59 ]. A recent study evaluated the effect of STF-083010, in a pristane-induced lupus model [ 60 ]. In comparison to the pristane group, the pristane+ STF-083010 group showed attenuation in splenomegaly, as well as a significant decrease in XBP1s protein expression in the spleen.…”

“…STF-083010 treatment also attenuated immunoglobulin deposition in the kidney and renal damage. No differential XBP1s expression was found in the kidneys among the three groups, suggesting that it is XBP1s activation in B cell, rather than in kidneys, that is driving renal damage [ 60 ].…”

Hyperbaric Oxygen Ameliorates The Expression of Tumor Growth Factor-β and Malondialdehyde in Pristane-induced Lupus Nephritis Mice Model

“…Therefore, this study was conducted to determine whether HBO ameliorates inflammation in LN by diminishing MDA and expanding TGF-β levels. Since LN model mice with pristane injection have been commonly used, and known to be the best model to explore LN (31)(32)(33), hence the same model was used for this study.…”