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Immune-Mediated Nephropathy and Systemic Autoimmunity in Mice Does Not Require Receptor Interacting Protein Kinase 3 (RIPK3)

View Article: PubMed Central - PubMed

ABSTRACT

Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates. A second pathway mediating necrosis involves Receptor-Interacting Serine-Threonine Kinase 3 (RIPK3); in this study we sought to investigate the impact of RIPK3 on the development of lupus and nephritis in both sexes. To this end, we used two inducible murine models of lupus: chronic graft versus host disease (cGvHD) and pristane-induced lupus; and nephrotoxic serum (NTS)-induced nephritis as a model of immune mediated nephropathy. We found that the absence of RIPK3 has neither positive nor negative impact on the disease development or progression of lupus and nephritis in all three models, and in both male and female mice. We conclude that RIPK3 is dispensable for the pathogenesis of lupus and immune mediated nephropathy as to accelerate, worsen or ameliorate the disease.

No MeSH data available.


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Absence of RIPK3 does not affect the development of autoimmunity induced by cGvHD or pristane.(A) After induction of cGvHD, anti-dsDNA and anti-chromatin levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group (pooled from two experiments) and all p-values were >0.05 (T-test). Autoantibody levels of PBS-treated mice are represented by the dotted line. (B) After cGVHD induction, total IgG levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group and all p-values were >0.05 (T-test). Total IgG levels were increased at 3 and 6 weeks compared to pre-bleed (T-test). Pre-bleed vs. 3 weeks: * p≤0.05, ** p≤ 0.01. Pre-bleed vs. 6 weeks: # p≤0.05.
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pone.0163611.g001: Absence of RIPK3 does not affect the development of autoimmunity induced by cGvHD or pristane.(A) After induction of cGvHD, anti-dsDNA and anti-chromatin levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group (pooled from two experiments) and all p-values were >0.05 (T-test). Autoantibody levels of PBS-treated mice are represented by the dotted line. (B) After cGVHD induction, total IgG levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group and all p-values were >0.05 (T-test). Total IgG levels were increased at 3 and 6 weeks compared to pre-bleed (T-test). Pre-bleed vs. 3 weeks: * p≤0.05, ** p≤ 0.01. Pre-bleed vs. 6 weeks: # p≤0.05.

Mentions: We first tested whether RIPK3 plays a role in inducing lupus autoimmunity during cGvHD. This murine model of lupus is dependent on allogeneic T cell help and tests the activation of endogenous autoreactive B cells and their production of autoantibodies directed toward nuclear components [20], which are a hallmark of lupus disease and major players in the initiation of lupus nephritis [4]. We induced cGvHD in B6 and RIPK3-/- male and female mice by injecting 108 allogeneic Bm12 splenocytes. After 6 weeks from the induction of cGvHD, mice from both strains, males and females, developed similar levels of anti-dsDNA and anti-chromatin autoantibodies (Fig 1A). The mice also did not develop renal disease as shown by no increase in proteinuria or BUN values (data not shown) and healthy kidney histology (S1 Fig); however mild splenomegaly was observed (S1 Fig). We also measured total serum IgG levels after cGvHD and found the characteristic polyclonal increase in both strains, demonstrating as similar overall response. (Fig 1B). Taken together, these results indicate that RIPK3 does not play a significant role in polyclonal activation and autoantibody production in the lupus-like disease induced during cGvHD.


Immune-Mediated Nephropathy and Systemic Autoimmunity in Mice Does Not Require Receptor Interacting Protein Kinase 3 (RIPK3)
Absence of RIPK3 does not affect the development of autoimmunity induced by cGvHD or pristane.(A) After induction of cGvHD, anti-dsDNA and anti-chromatin levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group (pooled from two experiments) and all p-values were >0.05 (T-test). Autoantibody levels of PBS-treated mice are represented by the dotted line. (B) After cGVHD induction, total IgG levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group and all p-values were >0.05 (T-test). Total IgG levels were increased at 3 and 6 weeks compared to pre-bleed (T-test). Pre-bleed vs. 3 weeks: * p≤0.05, ** p≤ 0.01. Pre-bleed vs. 6 weeks: # p≤0.05.
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pone.0163611.g001: Absence of RIPK3 does not affect the development of autoimmunity induced by cGvHD or pristane.(A) After induction of cGvHD, anti-dsDNA and anti-chromatin levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group (pooled from two experiments) and all p-values were >0.05 (T-test). Autoantibody levels of PBS-treated mice are represented by the dotted line. (B) After cGVHD induction, total IgG levels were similar between B6 and RIPK3-/- mice in both males and females. Data are represented as Mean ± SEM of 10 mice per group and all p-values were >0.05 (T-test). Total IgG levels were increased at 3 and 6 weeks compared to pre-bleed (T-test). Pre-bleed vs. 3 weeks: * p≤0.05, ** p≤ 0.01. Pre-bleed vs. 6 weeks: # p≤0.05.
Mentions: We first tested whether RIPK3 plays a role in inducing lupus autoimmunity during cGvHD. This murine model of lupus is dependent on allogeneic T cell help and tests the activation of endogenous autoreactive B cells and their production of autoantibodies directed toward nuclear components [20], which are a hallmark of lupus disease and major players in the initiation of lupus nephritis [4]. We induced cGvHD in B6 and RIPK3-/- male and female mice by injecting 108 allogeneic Bm12 splenocytes. After 6 weeks from the induction of cGvHD, mice from both strains, males and females, developed similar levels of anti-dsDNA and anti-chromatin autoantibodies (Fig 1A). The mice also did not develop renal disease as shown by no increase in proteinuria or BUN values (data not shown) and healthy kidney histology (S1 Fig); however mild splenomegaly was observed (S1 Fig). We also measured total serum IgG levels after cGvHD and found the characteristic polyclonal increase in both strains, demonstrating as similar overall response. (Fig 1B). Taken together, these results indicate that RIPK3 does not play a significant role in polyclonal activation and autoantibody production in the lupus-like disease induced during cGvHD.

View Article: PubMed Central - PubMed

ABSTRACT

Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates. A second pathway mediating necrosis involves Receptor-Interacting Serine-Threonine Kinase 3 (RIPK3); in this study we sought to investigate the impact of RIPK3 on the development of lupus and nephritis in both sexes. To this end, we used two inducible murine models of lupus: chronic graft versus host disease (cGvHD) and pristane-induced lupus; and nephrotoxic serum (NTS)-induced nephritis as a model of immune mediated nephropathy. We found that the absence of RIPK3 has neither positive nor negative impact on the disease development or progression of lupus and nephritis in all three models, and in both male and female mice. We conclude that RIPK3 is dispensable for the pathogenesis of lupus and immune mediated nephropathy as to accelerate, worsen or ameliorate the disease.

No MeSH data available.


Related in: MedlinePlus