Lupus erythematosus Graft-versus-Host Model of Systemic Nephritis in the Chronic Instrumental in the Pathogenesis of TWEAK/Fn14 Interactions Are (original) (raw)
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Immunology Letters, 2009
The cytokine TWEAK demonstrates potent kidney proinflammatory and proliferative effects. Recently, we have shown that interactions of TWEAK with its receptor Fn14 are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host (cGVH) induced model of lupus. Fn14 is expressed by macrophages and resident kidney cells; we hypothesized that TWEAK binding to both cell types contributes to the pathogenesis of lupus nephritis. To address this question, we generated bone marrow chimaeras and compared the progression of nephritis during cGVH induced lupus in mice expressing Fn14 only on bone marrow-derived cells, versus mice displaying Fn14 only on non-bone marrow-derived cells. While Fn14 deficiency did not significantly affect autoantibody titers, Fn14 deficiency on bone marrowderived cells did not inhibit nephritis initiation in mice with Fn14 sufficient non-hematopoeitic cells. Conversely, expression of Fn14 only on bone marrow-derived cells resulted in a delayed, milder disease course. To further explore the role of macrophages, we depleted macrophages during cGVH induction. Surprisingly, we found that macrophage depleted mice displayed significantly increased titers of anti-DNA antibodies and worse kidney disease. We conclude that the presence of Fn14 on resident kidney cells alone may be sufficient to initiate nephritis in this murine model of lupus.
Journal of the American Society of Nephrology, 2014
TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26-38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.
IFN- Confers Resistance of Systemic Lupus Erythematosus Nephritis to Therapy in NZB/W F1 Mice
The Journal of Immunology, 2011
The critical role of IFN-a in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-a in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-a, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-a-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-a challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of shortlived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-a renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.
The cytokine TWEAK modulates renal tubulointerstitial inflammation
Journal of the …, 2008
TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. In addition to binding and activating the fibroblast growth factor-inducible 14 receptor, TWEAK may regulate apoptosis, proliferation, and inflammation; however, the role of this system in kidney injury is unknown. In vitro, it was found that TWEAK induced the sustained activation of NF-B in a murine tubular epithelial cell line (MCT). NF-B activation was associated with degradation of IB-␣; translocation of RelA to the nucleus; and increased mRNA and protein expression of monocyte chemoattractant protein-1, RANTES, and IL-6. Similarly, in vivo, the systemic administration of TWEAK induced renal NF-B activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IB-␣ degradation, inhibited TWEAK-induced NF-B activation and prevented the aforementioned changes in vitro and in vivo. After folic acid-induced acute kidney injury, fibroblast growth factor-inducible 14 expression increased in mouse tubular epithelium. Neutralization of TWEAK decreased the expression of chemokines in tubular cells and reduced interstitial inflammation. In conclusion, TWEAK has NF-Bdependent proinflammatory effects on tubular epithelial cells in vitro and in vivo. Moreover, blockade of TWEAK reduces tubular chemokine expression and macrophage infiltration, suggesting that TWEAK modulates acute kidney injury by regulating the inflammatory response.
Cytokine cooperation in renal tubular cell injury: The role of TWEAK
Kidney International, 2006
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the TNF superfamily. TWEAK activates the Fn14 receptor, and may regulate apoptosis, proliferation, and inflammation, processes that play a significant role in pathological conditions. However, there is little information on the function and regulation of this system in the kidney. Therefore, TWEAK and Fn14 expression were studied in cultured murine tubular epithelial MCT cells and in mice in vivo. The effect of TWEAK on cell death was determined. We found that TWEAK and Fn14 expression was increased in experimental acute renal failure induced by folic acid. Cultured tubular cells express both TWEAK and the Fn14 receptor. TWEAK did not induce cell death in non-stimulated tubular cells. However, in cells costimulated with TNFa/interferon-gamma, TWEAK induced apoptosis through the activation of the Fn14 receptor. Apoptosis was associated with activation of caspase-8, caspase-9, and caspase-3, Bid cleavage, and evidence of mitochondrial injury. There was no evidence of endoplasmic reticulum stress. A pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp prevented TWEAK-induced apoptosis, but it sensitized cells to necrosis via generation of reactive oxygen species. In conclusion, cooperation between inflammatory cytokines results in tubular cell death. TWEAK and Fn14 may play a role in renal tubular cell injury.
Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis
Clinical & Experimental Immunology, 2008
Imbalance of cytokine homeostasis is a prominent feature of both experimental and human systemic lupus erythematosus (SLE). Because interleukin (IL)-12 promotes interferon (IFN)-g production leading to polarization of peripheral cells toward a T helper (Th) 1 phenotype, we investigated its role in lupus nephritis (LN). Soluble Th1 and Th2 cytokines were measured by enzyme-linked immunosorbent assay (ELISA) in sera and urines of SLE patients and controls. Th1/Th2 peripheral lymphocyte polarization was determined by flow cytometry. Glomerular accumulation of IL-12 was evaluated by immunohistochemistry, whereas urinary IL-12 was evaluated by ELISA. Higher serum IL-12 levels in SLE were associated with LN, whereas IL-4 was unrelated to the renal damage. Peripheral cells from LN patients showed a Th1 phenotype with a high IFN-g expression that paralleled the severity of renal damage. IL-12 was present within glomerular mononuclear cells in classes IV and V LN, and its accumulation was correlated strongly with urinary levels. IL-12 overexpression in SLE may contribute to the development of LN. Both serum and urinary IL-12 elevation reflect its glomerular production and parallel Th1 polarization of peripheral T cells and high IFN-g production. In SLE patients, IL-12 measurement may thus be predictive of the development of LN.
Kidney International, 2021
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