TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis (original) (raw)
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Structure and Function of Renal Macrophages and Dendritic Cells From Lupus‐Prone Mice
Arthritis & Rheumatology, 2014
ObjectiveTo characterize renal macrophages and dendritic cells (DCs) in 2 murine models of lupus nephritis.MethodsWe used a bead‐based enrichment step followed by cell sorting to isolate populations of interest from young mice and nephritic mice. Cell morphology was examined by microscopy. Arginase and nitrite production was examined using biochemical assays. The antigen‐presenting functions of the cells were determined using mixed lymphocyte reactions. Selected cytokine, chemokine, and Toll‐like receptor (TLR) profiles were examined using real‐time quantitative polymerase chain reaction.ResultsWe identified 2 populations of macrophages and 3 populations of DCs in both of our murine models of lupus (NZB/NZW and [NZW × BXSB]F1 mice). F4/80high macrophages, which were resident in normal kidneys and found to be increased in number during nephritis, did not produce either arginase or nitrite upon cytokine stimulation and acquired a mixed proinflammatory and antiinflammatory functional p...
Macrophage depletion ameliorates nephritis induced by pathogenic antibodies
Journal of Autoimmunity, 2015
Objective-Kidney involvement affects 40-60% of patients with lupus and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. Methods-In this study, we investigated the role of macrophages in mice receiving rabbit antiglomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. Results-We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, or serum urea seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with LN. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Conclusions-Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.
Lupus, 2020
Background C4d, which is a serum complement cleavage product of the activated complement component C4, was found to be an accurate indicator of lupus activity compared to complement levels. Recently, macrophages have been considered to be pivotal members in the pathogenesis of lupus nephritis (LN). M2c-like macrophages have anti-inflammatory functions and promote fibrosis. Multiple studies have detected that LN is associated with an imbalance between the regulatory T cell (Treg) population and the inflammatory T helper subtypes. Methods We evaluated and scored the immunohistochemical expression of C4d, CD163-positive M2C-macrophages and Foxp3-expressing Tregs in 53 renal biopsies of LN. Their expression was scored and correlated with clinical and histological disease activity and chronicity. Results Class IV was the most prevalent class (50.9%), followed by class III (17%). PTC-C4d intensity score, CD163% of positive M2c macrophages and FOXP3% of positive Tregs were significantly co...
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.
The Journal of Immunology, 2002
Anti-DNA autoantibody production is a key factor in lupus erythematosus development; nonetheless, the link between glomerular anti-DNA autoantibody deposition and glomerulonephritis development is not understood. To study the inflammatory and destructive processes in kidney, we used IFN-␥ ؉/؊ MRL/lpr mice which produce high anti-DNA Ab levels but are protected from kidney disease. The results showed that defective macrophage recruitment to IFN-␥ ؉/؊ mouse kidney was not caused by decreased levels of monocyte chemoattractant protein-1, a chemokine that controls macrophage migration to MRL/lpr mouse kidney. To determine which IFN-␥-producing cell type orchestrates the inflammation pathway in kidney, we transferred IFN-␥ ؉/؉ monocyte/ macrophages or T cells to IFN-␥ ؊/؊ mice, which do not develop anti-DNA autoantibodies. The data demonstrate that IFN-␥ production by infiltrating macrophages, and not by T cells, is responsible for adhesion molecule up-regulation, macrophage accumulation, and inflammation in kidney, even in the absence of autoantibody deposits. Therefore, in addition to monocyte chemoattractant protein-1, macrophage-produced IFN-␥ controls macrophage migration to kidney; the degree of IFN-␥ production by macrophages also regulates glomerulonephritis development. Our findings establish the level of IFN-␥ secretion by macrophages as a link between anti-DNA autoantibody deposition and glomerulonephritis development, outline the pathway of the inflammatory process, and suggest potential treatment for disease even after autoantibody development.
The Journal of Immunology, 2011
Renal infiltration with mononuclear cells is associated with poor prognosis in systemic lupus erythematosus. A renal macrophage/ dendritic cell signature is associated with the onset of nephritis in NZB/W mice, and immune-modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. In nephritic NZB/W mice, renal F4/80 hi / CD11c int macrophages are located throughout the interstitium, whereas F4/80 lo /CD11c hi dendritic cells accumulate in perivascular lymphoid aggregates. We show here that F4/80 hi /CD11c int renal macrophages have a Gr1 lo /Ly6C lo /VLA4 lo /MHCII hi /CD43 lo / CD62L lo phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80 hi /CD11c int cells upregulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of autophagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1 lo monocytes indicates that these are the source of F4/80 hi /CD11c int macrophages. CD11c hi /MHCII lo dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80 hi /CD11c int population displays increased expression of proinflammatory, regulatory, and tissue repair/ degradation-associated genes at nephritis onset that reverses with remission induction. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.
CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis
Arthritis research & therapy, 2015
The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters. Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test. The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ...