Reversal of ongoing proteinuria in autoimmune mice by treatment with C‐reactive protein

Abstract

Objective. To examine the ability of injection of C-reactive protein (CRP) to treat systemic lupus erythematosus (SLE) in the (NZB ؋ NZW)F 1 (NZB/NZW) mouse and to use a nephrotoxic nephritis (NTN) model to further examine the mechanism of this activity.Methods. NZB/NZW mice were given a single injection of 200 g of CRP prior to disease onset or after the onset of high-grade proteinuria. Mice were monitored weekly for proteinuria and monthly for antidouble-stranded DNA (anti-dsDNA) antibodies. NTN was induced by immunization with rabbit IgG followed by rabbit anti-mouse glomerular basement membrane. Proteinuria was measured daily, and renal pathology was scored. CRP was injected at the time of disease induction or 9 days later.Results. Treatment of NZB/NZW mice with CRP prior to disease onset delayed the onset of high-grade proteinuria by 16 weeks (P < 0.0001) and prolonged survival by 13 weeks (P < 0.002). CRP treatment of NZB/NZW mice during acute disease rapidly decreased proteinuria, and the treated mice remained aproteinuric for at least 10 weeks. Control and CRP-treated mice developed similar levels of anti-dsDNA. In C57BL/6 mice, injection of CRP either before or after induction of NTN suppressed proteinuria and glomerular pathology. CRP was completely ineffective in treating NTN in interleukin-10 (IL-10)-deficient mice.Conclusion. CRP injection suppresses inflammation in the kidney in SLE and NTN. The requirement for IL-10 in this protection suggests that CRP must rapidly initiate an IL-10-dependent antiinflammatory process. These findings suggest that a major function of CRP during the acute-phase response is to limit tissue damage and modulate acute inflammation.

C-reactive protein functions as a negative regulator of macrophage activation induced by apoptotic DNA

“…Whether CRP/apopDNA could bind to Fcγ receptors on mouse macrophages remains to be investigated. In this study, we revealed that IL-10 in the culture supernatants of CRP/ apopDNA-induced macrophages inhibited apopDNA-induced macrophage activation in the context of SLE disease, which is consistent with a previous study on the effect of CRP treatment in SLE disease (Rodriguez et al, 2005). However, discrepancies might also exist over CRP-IL-10 relationship between our study and other group's (Singh et al, 2006), which might be due to the disparation of cell types, the Protein & Cell plus apopDNA (50 μg/mL) in a dual-chamber transwell.…”

“…As an important acute phase protein with an ability to bind to nuclear antigen, CRP has been reported to participate in modulating cytokine production and immune response mediated by macrophages in many diseases such as autoimmune disease, atherosclerosis, and immune thrombocytopenia (Rodriguez et al, 2005;Singh et al, 2006;Marjon et al, 2009). In the present study, we demonstrated that CRP functions as an important regulatory factor to modulate apopDNA-induced autoimmune response mediated by macrophages.…”

“…Although the precise mechanism involved in triggering autoimmune response to self antigens is largely unknown, there is now good experimental evidence for a link between the defective clearance of apoptotic cells, the released nuclear antigen or other debris and SLE disease associated with C1q or DNase deficiency (Taylor et al, 2000;Walport, 2000). More recently, C-reactive protein (CRP), a member of the pentraxin family with an ability to bind to nuclear antigens as well as to damaged membranes and microbial antigens (Du Clos, 1989), was found to play a key role in the protection from autoimmune disease (Ogden and Elkon, 2005;Rodriguez et al, 2005;. Moreover, CRP was a prototypic acute phase protein produced mainly in response to inflammation, infection, or tissue damage (Garlanda et al, 2005;Bottazzi et al, 2010) and was reported to recognize nuclear autoantigens released from apoptotic cells, opsonize them through interacting with cell-surface FcγR, thereby activating macrophage-mediated phagocytosis (Mold et al, 2001;Bottazzi et al, 2010).…”

Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan

“…Table III summarizes our findings in relation to what has been published regarding the treatment of lupus erythematosus in NZB/W F1 mice. To our knowledge, only the use of CTLA4Ig in combination with cyclophosphamide (CTX) (15,32) and administration of C-reactive protein (16) have demonstrated a reversal of defined high grade proteinuria with $300 mg/dl. However, a median survival of 73 wk in NZB/W F1-treated mice with established disease as seen in our experiments has not been described before.…”

“…The second type of study focusing on established disease initiated treatment from a defined highgrade proteinuria (grade 3+ and 4+ with at least $300 mg/dl), which requires individual treatment schedules for each mouse. Although this study design most likely reflects the clinical situation with patients with lupus, only a few of them exist (14)(15)(16).…”