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Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway.

Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Higgs R, Quintana FJ, Sjöstrand M, Eloranta ML, Ní Gabhann J, Winqvist O, Sundelin B, Jefferies CA, Rozell B, Kuchroo VK, Wahren-Herlenius M - J. Exp. Med. (2009)

Bottom Line: Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome.Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17).These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Karolinska Institute, Stockholm SE-171 77, Sweden.

ABSTRACT
Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52- mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

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Increased tissue inflammation in Ro52−/− mice. (A) Increased ear thickness in Ro52−/− (n = 5) compared with Ro52+/+ (n = 5) mice after Oxazolone challenge. (ANOVA mixed model). (B) Microphotographs of treated ears. Original magnification, 10×. Bars, 100 µm. (C) Flow cytometry analysis of draining lymph node cells in mice from A. (D) Cytokines in triplicate supernatants of cultures after in vitro stimulation with 1 µg/ml anti-CD3 of cells from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice analyzed by ELISA. IL-23R and FoxP3 expression in cells derived from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice was analyzed by RT-PCR and calculated relative to HPRT. Data in A–D are representative of three independent experiments. Error bars represent SEM.
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fig3: Increased tissue inflammation in Ro52−/− mice. (A) Increased ear thickness in Ro52−/− (n = 5) compared with Ro52+/+ (n = 5) mice after Oxazolone challenge. (ANOVA mixed model). (B) Microphotographs of treated ears. Original magnification, 10×. Bars, 100 µm. (C) Flow cytometry analysis of draining lymph node cells in mice from A. (D) Cytokines in triplicate supernatants of cultures after in vitro stimulation with 1 µg/ml anti-CD3 of cells from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice analyzed by ELISA. IL-23R and FoxP3 expression in cells derived from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice was analyzed by RT-PCR and calculated relative to HPRT. Data in A–D are representative of three independent experiments. Error bars represent SEM.

Mentions: To further study the hyperresponsive immune system of Ro52−/− mice in a more controlled manner, we tested the response in Ro52−/− mice to low doses of the contact-sensitizing agent Oxazolone. Mice lacking Ro52 had a significantly higher contact hypersensitivity to Oxazolone than Ro52+/+ mice, as measured by ear thickness (Fig. 3 A), with affected ears showing epidermal hyperplasia and inflammatory infiltrates consisting predominantly of neutrophils (Fig. 3 B). Analysis of lymphoid cell populations in the draining lymph nodes of the Ro52−/− mice treated with Oxazolone showed accumulation of T cells with an activated phenotype (Fig. 3 C) and production of high amounts of the proinflammatory cytokines IL-6, IL-12/IL-23p40, TNF-α, and IL-17 and IL-23R expression after application of Oxazolone (Fig. 3 D). Production of IFN-γ was not different between WT and Ro52−/− mice, and the frequency of FoxP3+ cells was not affected (Fig. 3 D). These data demonstrate that a lack of Ro52 leads to dysregulated tissue inflammation with enhanced generation of effector T cells that produce proinflammatory cytokines.


Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway.

Espinosa A, Dardalhon V, Brauner S, Ambrosi A, Higgs R, Quintana FJ, Sjöstrand M, Eloranta ML, Ní Gabhann J, Winqvist O, Sundelin B, Jefferies CA, Rozell B, Kuchroo VK, Wahren-Herlenius M - J. Exp. Med. (2009)

Increased tissue inflammation in Ro52−/− mice. (A) Increased ear thickness in Ro52−/− (n = 5) compared with Ro52+/+ (n = 5) mice after Oxazolone challenge. (ANOVA mixed model). (B) Microphotographs of treated ears. Original magnification, 10×. Bars, 100 µm. (C) Flow cytometry analysis of draining lymph node cells in mice from A. (D) Cytokines in triplicate supernatants of cultures after in vitro stimulation with 1 µg/ml anti-CD3 of cells from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice analyzed by ELISA. IL-23R and FoxP3 expression in cells derived from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice was analyzed by RT-PCR and calculated relative to HPRT. Data in A–D are representative of three independent experiments. Error bars represent SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2722164&req=5

fig3: Increased tissue inflammation in Ro52−/− mice. (A) Increased ear thickness in Ro52−/− (n = 5) compared with Ro52+/+ (n = 5) mice after Oxazolone challenge. (ANOVA mixed model). (B) Microphotographs of treated ears. Original magnification, 10×. Bars, 100 µm. (C) Flow cytometry analysis of draining lymph node cells in mice from A. (D) Cytokines in triplicate supernatants of cultures after in vitro stimulation with 1 µg/ml anti-CD3 of cells from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice analyzed by ELISA. IL-23R and FoxP3 expression in cells derived from draining lymph nodes of five Ro52−/− and five Ro52+/+ mice was analyzed by RT-PCR and calculated relative to HPRT. Data in A–D are representative of three independent experiments. Error bars represent SEM.
Mentions: To further study the hyperresponsive immune system of Ro52−/− mice in a more controlled manner, we tested the response in Ro52−/− mice to low doses of the contact-sensitizing agent Oxazolone. Mice lacking Ro52 had a significantly higher contact hypersensitivity to Oxazolone than Ro52+/+ mice, as measured by ear thickness (Fig. 3 A), with affected ears showing epidermal hyperplasia and inflammatory infiltrates consisting predominantly of neutrophils (Fig. 3 B). Analysis of lymphoid cell populations in the draining lymph nodes of the Ro52−/− mice treated with Oxazolone showed accumulation of T cells with an activated phenotype (Fig. 3 C) and production of high amounts of the proinflammatory cytokines IL-6, IL-12/IL-23p40, TNF-α, and IL-17 and IL-23R expression after application of Oxazolone (Fig. 3 D). Production of IFN-γ was not different between WT and Ro52−/− mice, and the frequency of FoxP3+ cells was not affected (Fig. 3 D). These data demonstrate that a lack of Ro52 leads to dysregulated tissue inflammation with enhanced generation of effector T cells that produce proinflammatory cytokines.

Bottom Line: Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome.Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17).These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Karolinska Institute, Stockholm SE-171 77, Sweden.

ABSTRACT
Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52- mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

Show MeSH
Related in: MedlinePlus