Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells

Zhang, Hui; Zhao, Chun‐Mei; Wang, Shuang; Huang, Yuefang; Wang, Hongyue; Zhao, Jijun; Yang, Niansheng

doi:10.1186/s12967-015-0536-7

Cited by 37 publications

(36 citation statements)

References 41 publications

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“…Healthy sera were used as controls. Polyclonal anti-dsDNA antibodies were isolated from sera of SLE patients and control IgG from healthy subjects by affinity chromatography as we previously described [ 25 ]. Immune complexes were precipitated with polyethylene glycol (3.5 % [wt/vol]).…”

Section: Methodsmentioning

confidence: 99%

Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages

Zhang

Guo

et al. 2016

J Transl Med

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BackgroundNLRP3 inflammasome has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The activation of NLRP3 inflammasome results in the production of IL-1β and the subsequent inflammation. Anti-dsDNA antibodies (anti-dsDNA Abs) play critical roles in the development and progression of SLE. However, the mechanism of NLRP3 inflammasome activation in SLE is still not known. This study investigated the activation of NLRP3 inflammasome stimulated by anti-dsDNA Abs in monocytes/macrophages from SLE patients.MethodsMonocytes/macrophages from SLE patients or healthy controls were stimulated with anti-dsDNA Ab-positive serum or purified anti-dsDNA Abs. Activation of inflammasome was measured by flow cytometry or Western blot. Anti-dsDNA Abs isolated from active SLE patients were injected into female (NZB × NZW) F1 mice and the activation of NLRP3 inflammasome and the frequencies of Th17 and Treg were examined.ResultsThe activity of caspase-1 was significantly increased in active SLE patients and was correlated with serum levels of anti-dsDNA Abs and disease activities. The concentrations of IL-1β and IL-17A were also significantly higher in SLE patients compared to healthy controls. Anti-dsDNA Ab-positive serum rather than healthy serum or RF (rheumatoid factor)-positive serum stimulated the activation of caspase-1 in monocytes. Anti-dsDNA Abs bound to TLR4 on macrophages and induced the production of ROS. Mitochondria-targeting antioxidant Mito-TEMPO, IκB kinase inhibitor peptide or TLR4 siRNA inhibited the activation of NLRP3 inflammasome and the secretion of IL-1β induced by anti-dsDNA Abs. Injection of anti-dsDNA Abs into (NZB × NZW) F1 mice resulted in increased caspase-1 activation and production of IL-1β and IL-17A. The Th17/Treg cell ratio also significantly increased following anti-dsDNA Ab injection.ConclusionsAnti-dsDNA Abs activated NLRP3 inflammasome in monocytes/macrophages from SLE patients by binding to TLR4 and inducing the production of mitochondrial ROS.

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Section: Methodsmentioning

confidence: 99%

Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages

Zhang

Guo

et al. 2016

J Transl Med

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“…The cellular penetration of antibodies is assisted by F(ab)′2 fragments with the mediation of the antigen-antibody binding region, which is also temperature-dependent and energy-consuming (70). Although the Fc fragment of an anti-DNA antibody contributes to its binding activity with monogamous bivalency, in which both Fab combining sites come into contact with DNA, the binding is not inhibited by the blockage of Fc receptor in mesangial cells (71, 72). In addition, the existence of manifold charged amino acids in CDRs is a specific feature of penetrating antibodies, which is explained by the energy-independent electrostatic interactions of arginine residues in the CDR2 and CDR3 with the negatively charged sulfated polysaccharides on the cell surface (68, 73), suggesting that cell penetration is an intrinsic property of anti-dsDNA antibodies.…”

Section: The Pathogenicity Of Anti-dsdna Antibodiesmentioning

confidence: 99%

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

2019

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Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

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“…T lymphocytes from SLE patients may be more susceptible to ER stress-induced apoptosis, related to defective BiP and autophagy ( 258 ). On the other hand, anti-double-stranded DNA antibodies, which are characteristic of lupus, induced both ER stress and cytokine production from human kidney mesangial cells ( 259 ). In systemic sclerosis, PBMC from patients showed upregulation of BiP, ATF4, ATF6, XBP1s, along with increased DNAJB1 and IFN-related genes.…”

Section: Implications For Autoimmunity and Autoinflammatory Diseasesmentioning

confidence: 99%

Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

2018

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Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defense against pathogens, but when aberrantly produced, may also drive pathologic inflammation. The UPR influences cytokine production on multiple levels, from stimulation of pattern recognition receptors, to modulation of inflammatory signaling pathways, and the regulation of cytokine transcription factors. This review will focus on the mechanisms underlying cytokine regulation by the UPR, and the repercussions of this relationship for infection and autoimmune/autoinflammatory diseases. Interrogation of viral and bacterial infections has revealed increasing numbers of examples where pathogens induce or modulate the UPR and implicated UPR-modulated cytokines in host response. The flip side of this coin, the UPR/ER stress responses have been increasingly recognized in a variety of autoimmune and inflammatory diseases. Examples include monogenic disorders of ER function, diseases linked to misfolding protein (HLA-B27 and spondyloarthritis), diseases directly implicating UPR and autophagy genes (inflammatory bowel disease), and autoimmune diseases targeting highly secretory cells (e.g., diabetes). Given the burgeoning interest in pharmacologically targeting the UPR, greater discernment is needed regarding how the UPR regulates cytokine production during specific infections and autoimmune processes, and the relative place of this interaction in pathogenesis.

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Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells

Cited by 37 publications

References 41 publications

Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages

Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

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