Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: Involvement of HMGB1 in anti-DNA antibody-induced renal injury

Qing, Xiaoping; Pitashny, Milena; Thomas, David B.; Barrat, Franck J.; Hogarth, P. Mark; Putterman, Chaim

doi:10.1016/j.imlet.2008.08.007

Cited by 73 publications

(70 citation statements)

References 59 publications

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“…and RAGE, exhibited a synergistic effect on the upregulation of proinflammatory gene expression in renal mesangial cells in vitro and chemokine expression in kidneys of BALB/c mice (42). However, whether HMGB1 plays a role in autoantibody produc- (14)(15)(16).…”

Section: Discussionmentioning

confidence: 97%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed “circulating DNA-containing ICs”), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.

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Section: Discussionmentioning

confidence: 97%

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Wen

Lin

Chen

et al. 2013

The Journal of Immunology

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“…First, the interaction of HMGB1 with RAGE is thought to participate in the progression of systemic disease by stimulating TLR9-mediated proliferation of autoreactive B cell clones (22). Second, RAGE expression is upregulated in the kidneys of SLE patients (23), and signaling through HMGB1-RAGE activates mesangial cells in vitro, therefore suggesting a role for the RAGE axis in the progression of lupus nephritis (24). Furthermore, other alarmin molecules such as C3a as well as CpG DNA oligos are able to bind to RAGE and stimulate IFN-a production by human PBMCs in a RAGE-dependent manner (25,26).…”

Section: Discussionmentioning

confidence: 99%

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

Goury

Meghraoui-Kheddar

Belmokhtar

et al. 2015

The Journal of Immunology

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The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3+B220+CD4−CD8− autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE−/− mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE−/− mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3+B220+CD4−CD8− T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.

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“…Notably, HMGB1 is also part of immunostimulatory complexes that bind to and activate autoreactive B cells (37). Finally, HMGB1-DNA complexes induce cytokine secretion from mesangial cells in vitro (92). Serum HMGB1 levels are higher in patients with scleroderma and correlate with skin fibrosis and impaired lung function (93).…”

Section: Hmgb1 In Chronic Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

HMGB1 and RAGE in Inflammation and Cancer

Sims¹,

Rowe²,

Rietdijk

et al. 2010

Annu. Rev. Immunol.

1,244

1,096

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The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.

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Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: Involvement of HMGB1 in anti-DNA antibody-induced renal injury

Cited by 73 publications

References 59 publications

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

Autoantibody Induction by DNA-Containing Immune Complexes Requires HMGB1 with the TLR2/MicroRNA-155 Pathway

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

HMGB1 and RAGE in Inflammation and Cancer

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