Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Goury, Antoine; Meghraoui-Kheddar, Aïda; Belmokhtar, Karim; Vuiblet, Vincent; Ortillon, Jeremy; Jaisson, Stéphane; Devy, Jérôme; Naour, Richard Le; Tabary, Thierry; Cohen, Jacques H. M.; Schmidt, Ann‐Marie; Rieu, Philippe; Touré, Fatouma

doi:10.4049/jimmunol.1402342

Cited by 17 publications

(15 citation statements)

References 49 publications

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“…Next, to examine the activation status of the CD4 + and CD8 + T cells, we determined the early activation marker CD69 expression. Activated CD69 + CD4 + T cells were increased in Fas lpr/lpr mice as previously reported [36], but SH3BP2 de ciency signi cantly suppressed the activation of CD4 + T cells in the spleen (Fig. 3c).…”

Section: Sh3bp2 De Ciency Blunts the Aberrant Accumulation Of Cd3 + Bsupporting

confidence: 86%

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Kawahara

Mukai

Iseki

et al. 2020

Preprint

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Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways, including Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model.Methods: For the lupus model, we used Faslpr/lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody and rheumatoid factor, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice.Conclusions: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cell differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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Section: Sh3bp2 De Ciency Blunts the Aberrant Accumulation Of Cd3 + Bsupporting

confidence: 86%

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Kawahara

Mukai

Iseki

et al. 2020

Preprint

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“…However, as discussed, in the context of murine models of SLE, TLR9 deficiency exacerbates disease outcome. Remarkably, RAGE-deficient B6/lpr mice also develop more severe nephritis (77). Whether FasL-induced HMGB1, under the appropriate conditions, can also contribute to a TLR9-mediated negative feedback loop is yet one more question that can be addressed in future studies.…”

Section: Discussionmentioning

confidence: 97%

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

Mande¹,

Zirak²,

Ko³

et al. 2018

Journal of Clinical Investigation

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Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

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“…These studies suggested that RAGE reduces the accumulation of autoreactive CD3(+)B220(+)CD4(−)CD8(−) T lymphocytes, and that deletion of Ager exacerbates lymphoproliferative syndrome, autoimmunity, and organ injury. From the studies, we may infer that RAGE is able to rescue apoptosis of T lymphocytes when Fas/CD95 is not present or functional [67]. …”

Section: 0 Rage and Roles In Autoimmunity And Chronic Inflammationmentioning

confidence: 99%

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Ramasamy

Shekhtman

Schmidt

2015

Expert Opinion on Therapeutic Targets

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Introduction This review focuses on the multi-ligand receptor of the immunoglobulin superfamily, receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging. Areas Covered In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; tumors and Alzheimer’s disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule, the formin DIAPH1. Physico-chemical evidence by which the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences, is also reviewed. Expert Opinion We discuss the modalities of RAGE antagonism currently in pre-clinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging in which RAGE ligands accumulate and signal.

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Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

Cited by 17 publications

References 49 publications

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

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