Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/<i>lpr</i>Mice

Bao, Lihua; Haas, Mark; Boackle, Susan A.; Kraus, Damian; Cunningham, Patrick N.; Park, Pierce; Alexander, Jessy J.; Anderson, Randall K.; Culhane, Kristin; Holers, V. Michael; Quigg, Richard J.

doi:10.4049/jimmunol.168.7.3601

Cited by 105 publications

(78 citation statements)

References 46 publications

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“…Hypocomplementemia and deposition of complement activation fragments in glomeruli suggest that complement activation also contributes to the pathogenesis of the proliferative and sclerosing glomerular disease evident in these mice. The relevance of complement to experimental lupus nephritis is also supported by our previous studies in which we systematically inhibited C3/C5 activation in MRL/lpr mice, which led to a reduction in renal disease and prolonged survival in complement-inhibited mice compared to controls [8,9].…”

Section: Introductionsupporting

confidence: 56%

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

et al. 2005

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Section: Introductionsupporting

confidence: 56%

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

et al. 2005

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“…In previous studies, we found that complement inhibition with Crry reduced the incidence of renal failure and severe proteinuria in MRL/lpr mice, in conjunction with a significant reduction of glomerulosclerosis (12,13). These results suggest that complement inhibition with Crry acts to reduce the production and/or promote the degradation of extracellular matrix (ECM) in kidney, preventing severe proteinuria and renal failure in these mice.…”

mentioning

confidence: 89%

Excessive Matrix Accumulation in the Kidneys of MRL/lpr Lupus Mice Is Dependent on Complement Activation

Bao¹,

Zhou²,

Holers³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. Complement inhibition with Crry as the recombinant protein Crry-Ig has been demonstrated to prevent MRL/MpJ-Tnfrsf6 lpr (MRL/lpr) mice from developing proteinuria and renal failure. Crry-Ig-treated mice also showed less glomerulosclerosis compared with control MRL/lpr mice. To clarify how complement inhibition with Crry might affect renal scarring in lupus nephritis, gene transcript profiling was performed comparing Crry-Ig-treated MRL/lpr mice to controltreated MRL/lpr mice as well as to the MRL/ϩ strain control. Altered gene expression was confirmed by quantitative PCR, and protein quantity with either immunoblotting or immunofluorescence microscopy. Collagens I, III, IV, and VI were overexpressed in control MRL/lpr mice, whereas complement inhibition with Crry reduced the overexpression of these extracellular matrix components toward normal. Plasminogen activator inhibitor 1, connective tissue growth factor, and TGF-␤1 were upregulated in MRL/lpr mice compared with MRL/ϩ mice and were normalized by Crry-Ig treatment, suggesting that the product of these genes may contribute to the progressive glomerulosclerosis in MRL/lpr mice in a complement-dependent fashion. Thus, complement inhibition with Crry has a prominent effect on matrix-related genes and proteins, which translates into improvement in functional renal disease.The MRL/MpJ-Tnfrsf6 lpr (MRL/lpr) strain is a murine model of human systemic lupus erythematosus. These mice develop many features of human systemic lupus erythematosus, including autoantibodies, hypocomplementemia, and proliferative glomerulonephritis (GN) (1,2). MRL/lpr mice differ from the lupus-prone congenic MRL/ϩ strain by the nearly complete absence of the apoptosis-promoting membrane Fas protein, which is due to a retroviral insertion in the Tnfrsf6 (Fas) gene (3,4). In contrast to MRL/lpr mice, MRL/ϩ mice develop lupus very late in life, including only mild renal disease. Renal disease in MRL/lpr mice has similar features to the human disease it models, with mesangial proliferative GN early in disease and diffuse proliferative and crescentic GN later in the course. Ultimately, glomerulosclerosis and renal failure occur in the terminal phase of disease and are believed to cause death in these mice (5). Decreased serum C3 levels and deposition of C3 activation fragments and other complement components in kidney suggest that complement is involved in the pathogenesis of murine as well as human lupus nephritis (2).Complement activation can proceed via the classical, alternative, or mannose-binding lectin pathways (6). Activation through each of the three pathways leads to cleavage of C3 with generation of the proinflammatory and regulatory fragments C3a and C3b. C3b attaches covalently to immune complexes, which is followed by C5 binding and its cleavage to C5a and C5b. The former is a potent in...

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“…12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairment in the elderly, and the FH polymorphism Y402H is the major genetic risk factor for AMD development. 15,16 The presence of drusen (extracellular deposits of debris) between the retinal pigmented epithelium (RPE) and the choroid of the macula is characteristic of AMD.…”

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confidence: 99%

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

et al. 2016

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Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH − / − MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH +/+ littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration. Factor H (FH), one of the most abundant plasma proteins, is the major soluble inhibitor of the alternative complement pathway. Apoptotic cells bind FH while triggering complement activation by binding of C1 complex, which ensures efficient opsonization and removal of apoptotic debris but prevents excessive complement activation and inflammation. 1,2 Dysregulation of complement contributes significantly to the pathology of many diseases. 3 Recently, novel roles and intracellular location for complement have been identified suggesting that its functions exceed our current understanding. 4 After previously identifying the ligands for FH on the apoptotic cell surface as dsDNA, histones and annexin A2, 5 we sought to explore the functional consequences of the FH-apoptotic cell interaction in the context of the chronic autoimmune disorder systemic lupus erythematosus (SLE) and age-related macular degeneration (AMD). Aberrant apoptosis and impaired clearance of apoptotic cells are of central importance in the pathogenesis of SLE and lead to formation of autoantibodies. 6-8 Anti-chromatin autoantibodies are a hallmark of SLE and anti-annexin A2 autoantibodies are also frequently observed in SLE patients. 9 Interestingly, the corresponding autoantigens are exactly those that we identified as ligands for FH on the apoptotic cell surface, suggesting a possibility of disturbance of FH function in SLE. Glomerulonephritis is one typical manifestation of human SLE 10 and mutations in FH and another complement inhibitor CD46 are associated with earlier onset of nephritis in SLE patients. 11 FH-deficient (CFH − / − ) mice spontaneously develop membranoproliferative glomerulonephritis, which is dependent on C3 activation. 12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairm...

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Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lprMice

Cited by 105 publications

References 46 publications

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

Excessive Matrix Accumulation in the Kidneys of MRL/lpr Lupus Mice Is Dependent on Complement Activation

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

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