scholarly journals HMGB1 Activates Myeloid Dendritic Cells by Up-Regulating mTOR Pathway in Systemic Lupus Erythematosus

2021 ◽  
Vol 8 ◽  
Author(s):  
Xinghui Song ◽  
Hui Zhang ◽  
Yun Zhao ◽  
Yuanzhen Lin ◽  
Qiya Tang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Mtor Pathway ◽  
Systemic Lupus ◽  
Myeloid Dendritic Cells ◽  
Hla Dr ◽  
Tnf Α ◽  
Hmgb1 Expression ◽  
Pro Inflammatory Cytokines

Research has shown that HMGB1 can activate dendritic cells (DCs), but its molecular mechanisms are not clear. In this study, we reported that the myeloid dendritic cells (mDCs) were activated in the peripheral blood of SLE patients, and the activation of mDCs was associated with the up-regulation of HMGB1 and mTOR. After stimulated by HMGB1, expression of mTOR and its substrates P70S6K and 4EBP1 in dendritic cells increased considerably (P < 0.01). The expression of HLA-DR, CD40, and CD86 on dendritic cells also significantly increased following these stimuli (P < 0.01). In addition, stimulation with HMGB1 enhanced cytokine (IL-1β, IL-6, and TNF-a) production in dendritic cells. In contrast, the HMGB1-mediated expression of HLA-DR, CD40, and CD86 on dendritic cells and production of IL-1β, IL-6, and TNF-α were reduced by rapamycin. Rapamycin can inhibit HMGB1-induced activation of mDCs and secretion of pro-inflammatory cytokines. These findings indicated that HMGB1activates mDCs by up-regulating the mTOR pathway in SLE.

Stable expression ratios of five pyroptosis-inducing cytokines in the spleen and thymus of mice showed potential immune regulation at the organ level

Lupus ◽  
2020 ◽  
Vol 29 (3) ◽  
pp. 290-302
Author(s):  
H Fan ◽  
S Zhang ◽  
N Li ◽  
P Fan ◽  
X Hu ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Immune Regulation ◽  
Interleukin 18 ◽  
Systemic Lupus ◽  
Tnf Α ◽  
Organ Level ◽  
Pro Inflammatory Cytokines

Background The immune system is one of the most complex regulatory systems in the body and is essential for the maintenance of homeostasis. Despite recent breakthroughs in immunology, the regulation of the immune system and the etiology of autoimmune diseases such as lupus remain unclear. Systemic lupus erythematosus is a systemic autoimmune disease with abnormally and inconsistently expressed pro-inflammatory cytokines. Pyroptosis is a pro-inflammatory form of programmed cell death that is associated with systemic lupus erythematosus. The thymus and spleen are important immune organs involved in systemic lupus erythematosus. Therefore, this study investigated the difference in expression of pyroptosis-inducing pro-inflammatory cytokines between the spleen and thymus in lupus model mice and in control mice, to describe immune regulation at the organ level. Objective To investigate differences in the expression of pyroptosis-inducing cytokines in the spleen and thymus and to explore immune regulatory networks at the organ level. Methods Two groups of lupus mice and two groups of control mice were utilized for this study. Using the thymus and spleen of experimental animals, mRNA expression levels of five pyroptosis-inducing cytokines (interleukin 1β, interleukin 18, NLRP3, caspase-1 and TNF-α) were determined via quantitative polymerase chain reaction. In addition, tissue distribution of these cytokines was investigated via immunohistochemistry. Results All five pyroptosis-inducing inflammatory cytokines showed higher expression in the spleen than in the thymus ( p < 0.05). Moreover, the spleen/thymus expression ratios of all five pyroptosis-inducing cytokines were not statistically different between the four experimental groups. Expression of all five cytokines exhibited a stable ratio (spleen/thymus ratios). This distinctive stable spleen/thymus ratio was consistent in all four experimental groups. The stable spleen/thymus ratios of the five inflammatory cytokines were as follows: interleukin 1β (2.02 ± 0.9), interleukin 18 (2.07 ± 1.06), caspase-1 (1.93 ± 0.66), NLRP3 (3.14 ± 1.61) and TNF-α (3.16 ± 1.36). Immunohistochemical analysis showed the cytokines were mainly expressed in the red pulp region of the spleen and the medullary region of the thymus, where immune-activated cells aggregated. Conclusion The stable spleen/thymus expression ratios of pyroptosis-inducing cytokines indicated that immune organs exhibit strictly regulated functions to maintain immune homeostasis and adapt to the environment.

scholarly journals Reduced blood BDCA-2+ (lymphoid) and CD11c+ (myeloid) dendritic cells in systemic lupus erythematosus

2005 ◽  
Vol 142 (1) ◽  
pp. 84-91 ◽  
Author(s):  
K. Migita ◽  
T. Miyashita ◽  
Y. Maeda ◽  
H. Kimura ◽  
M. Nakamura ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Myeloid Dendritic Cells

scholarly journals Phenotypic and Functional Consequences of PLT Binding to Monocytes and Its Association with Clinical Features in SLE

2021 ◽  
Vol 22 (9) ◽  
pp. 4719
Author(s):  
Anaís Mariscal ◽  
Carlos Zamora ◽  
Berta Magallares ◽  
Tarek Carlos Salman-Monte ◽  
Mª Àngels Ortiz ◽  
...  
Keyword(s):  
Immune Cells ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Hla Dr ◽  
Healthy Donors ◽  
Tnf Α ◽  
Autoimmune Conditions ◽  
Functional Consequences ◽  
Functional Features ◽  
Dsdna Antibodies

Platelets (PLTs) can modulate the immune system through the release of soluble mediators or through interaction with immune cells. Monocytes are the main immune cells that bind with PLTs, and this interaction is increased in several inflammatory and autoimmune conditions, including systemic lupus erythematosus (SLE). Our aim was to characterize the phenotypic and functional consequences of PLT binding to monocytes in healthy donors (HD) and in SLE and to relate it to the pathogenesis of SLE. We analyzed the phenotypic and functional features of monocytes with non-activated and activated bound PLTs by flow cytometry. We observed that monocytes with bound PLTs and especially those with activated PLTs have an up-regulated HLA-DR, CD86, CD54, CD16 and CD64 expression. Monocytes with bound PLTs also have an increased capacity for phagocytosis, though not for efferocytosis. In addition, monocytes with bound PLTs have increased IL-10, but not TNF-α, secretion. The altered phenotypic and functional features are comparable in SLE and HD monocytes and in bound PLTs. However, the percentages of monocytes with bound PLTs are significantly higher in SLE patients and are associated with undetectable levels of anti-dsDNA antibodies and hematuria, and with normal C3 and albumin/creatinine levels. Our results suggest that PLTs have a modulatory influence on monocytes and that this effect may be highlighted by an increased binding of PLTs to monocytes in autoimmune conditions.

scholarly journals 4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

2018 ◽  
Vol 51 (2) ◽  
pp. 979-990 ◽  
Author(s):  
Chun Tang ◽  
Xiaohua Wang ◽  
Yingying Xie ◽  
Xiaoyan Cai ◽  
Na Yu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Nuclear Factor ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Human Macrophages ◽  
Tnf Α ◽  
Blood Mononuclear Cells ◽  
Pro Inflammatory Cytokines

Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

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