Rapamycin alleviates renal damage in mice with systemic lupus erythematosus through improving immune response and function

Song, Xinghui; Gao, Jinglin; Hui-cong, Liu; Li, Xiuhua; Tang, Kaijiang

doi:10.1016/j.biopha.2021.111289

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…Gu's study ( 31 ) demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. This result is consistent with our previous research ( 32 ).…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 94%

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

et al. 2021

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“…This hypothesis is consistent with the known mechanism of the action of rapamycin, which is the suppression of the proliferation of interleukin-2-stimulated-T lymphocytes via inhibition of mTOR [ 53 ]; 3) mTOR activation and aberrant autophagy is responsible for skewing of T cell lineage specification in SLE [ 54 ]. Treatment with rapamycin improved the immune response and function, and reduced the proportion of Th1, Th2, Th17, and DN T cells in the spleen, kidney, and peripheral blood [ 33 , 45 , 55 ]; 4) Treatment with rapamycin blocked the IL-4 production and necrosis of DN T cells, which can release immunogenic nuclear materials [ 56 ]; 5) Rapamycin reduced intrarenal CCL5 expression and decreased CD4 + , CD8 + T cell, B cell, and macrophage infiltration in the kid- neys [ 32 ]; 6) Rapamycin reverses the senescent phenotype and improves immune regulation of mesenchymal stem cells from LN [ 57 ]; 7) mTORC1 and mTORC2 are markedly activated, which may underlie the diminished autophagy in podocytes, mesangial cells, endothelial cells and tubular epithelial cells of LN patients. Autophagy is protective within podocytes and required for recovery from autoantibody-induced podocyte injury [ 54 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is the allosteric inhibitor of the mechanistic target of rapamycin (mTOR) and can form an FRB domain with the FKBP12 protein to inhibit the activity of mTOR [29,30]. The beneficial effect of rapamycin on LN has been confirmed in both mouse models and patients [31][32][33]. However, the specific mechanisms underlying rapamycin's alleviation of LN injury and the effect of rapamycin on Treg cells and TIM-3 are not yet completely understood.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model

Gao¹,

Fan²,

Li³

et al. 2022

cejoi

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Lupus nephritis (Ln) is a severe consequence of systemic lupus erythematosus (sLE) and is an important driver of morbidity and mortality in sLE. Treg cells and TiM-3 play an important role in the pathogenesis of Ln. The beneficial effect of rapamycin on Ln has been confirmed in both mouse models and patients, but the effect of rapamycin on Treg cells and TiM-3 is not yet completely understood. in this study, rapamycin treatment attenuated proteinuria, histological damage, and renal deposition of C3, and improved renal function. spleen and renal draining lymph node weight and serum levels of anti-dsDna antibodies were also improved by rapamycin. furthermore, the frequency of Treg cells and Treg functional molecules, such as cytotoxic T cell antigen 4 (CTLa-4), interleukin 10 (iL-10), and transforming growth factor β1 (Tgf-β1), increased significantly after treatment with rapamycin in MRL/lpr mice. We also found that expression of TiM-3 was significantly decreased in CD4+ T cells and Treg cells in mice treated with rapamycin. in summary, the study demonstrated that rapamycin treatment induced preferential expansion of CD4+CD25+foxp3+ Tregs with increased expression of , and decreased TiM-3 expression, thereby ameliorating lupus nephritis in the MRL/lpr mouse model.

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“…A mouse experiment found that treatment with rapamycin, an allosteric inhibitor of the mTOR, not only reduces the proportion of Th1, Th2 and Th17 cells but also boosts DCs to alleviate kidney damage in BALB/C mice with systemic lupus erythematosus (SLE) (Ref. 62 ). Furthermore, HIF-1 α is critical for the activation of T cells (Ref.…”

Section: Immune Cells and Non-immune Cells And Their Metabolic Charac...mentioning

confidence: 99%

“…Besides, treatment with mTOR inhibitor rapamycin, which inhibits glycolysis, can reduce the proportion of Th1, Th2 and Th17 cells and boost the proportion of DCs in the kidney to alleviate kidney damage in BALB/C mice with SLE (Ref. 62 ). However, in addition to inhibiting metabolic pathways of immune cells that can alleviate renal damage or renal fibrosis, so do non-immune cells.…”

Section: Treatments Targeting Immune Cells Metabolic Signature In Ckdmentioning

confidence: 99%

Metabolic signatures of immune cells in chronic kidney disease

Yang

Wang

et al. 2022

Expert Rev. Mol. Med.

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Immune cells play a key role in maintaining renal dynamic balance and dealing with renal injury. The physiological and pathological functions of immune cells are intricately connected to their metabolic characteristics. However, immunometabolism in chronic kidney disease (CKD) is not fully understood. Pathophysiologically, disruption of kidney immune cells homeostasis causes inflammation and tissue damage via triggering metabolic reprogramming. The diverse metabolic characteristics of immune cells at different stages of CKD are strongly associated with their different pathological effect. In this work, we reviewed the metabolic characteristics of immune cells (macrophages, natural killer cells, T cells, natural killer T cells and B cells) and several non-immune cells, as well as potential treatments targeting immunometabolism in CKD. We attempt to elaborate on the metabolic signatures of immune cells and their intimate correlation with non-immune cells in CKD. 8Jie Li et al.

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Rapamycin alleviates renal damage in mice with systemic lupus erythematosus through improving immune response and function

Cited by 11 publications

References 32 publications

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

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

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model

Metabolic signatures of immune cells in chronic kidney disease

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