Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2–STAT3 signaling pathway

Dang, Wen-Zhen; Li, Hui; Jiang, Bing; Nandakumar, Kutty Selva; Liu, Kaifei; Liu, Lixin; Yu, Xiaochen; Tan, Huijing; Zhou, Chun

doi:10.1016/j.phymed.2019.152965

Cited by 41 publications

(32 citation statements)

References 33 publications

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“…Artesunate was shown to decrease MIF level in HUVEC culture with IFNα stimulation and in SLE patient-derived PBMC culture, partly through attenuating STAT1 phosphorylation, indicating a potential therapeutic effect of artesunate on SLE-associated atherosclerosis ( 56 ). Another study in vivo revealed that artesunate ameliorated the symptoms of lupus nephritis, decreased renal deposition of anti-dsDNA antibodies and suppressed the production of pathogenic cytokines through a reduction of follicular T helper cells (Tfh) and enhancement of follicular regulatory T cells (Tfr) as well as suppression of Jak2-Stat3 signaling pathway ( 57 ). Besides, SM934, an artemisinin derivative, extended the lifespan of MRL/lpr mice, relieved the lymphadenopathy symptoms, and suppressed B cell activation and plasma cell formation in vivo ( 58 ).…”

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

“…Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins control signal transduction of many cytokines and growth factors associated with cellular growth, survival and differentiation ( 71 ). Artesunate reportedly attenuated STAT1 phosphorylation in cultured HUVECs stimulated with IFNα ( 56 ) and suppressed phosphorylation of JAK2 and STAT3 in the kidney of MRL/lpr mice, resulting in an amelioration of the symptoms of lupus nephritis ( 57 ).…”

Section: The Effects Of Artemisinin and Its Derivatives On Cellular Signaling Pathwaysmentioning

confidence: 99%

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Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Qiu

Liu

et al. 2021

Front. Immunol.

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Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. In this aspect, tremendous progress has been made during the past five to seven years. Therefore, the present review summarizes recent studies that have explored the anti-inflammatory and immunomodulatory effects of ARTs on autoimmune diseases and transplant rejection. In this review, we also discuss the cellular and molecular mechanisms underlying the immunomodulatory effects of ARTs. Recent preclinical studies will help lay the groundwork for clinical trials using ARTs to treat various immune-based disorders, especially autoimmune diseases.

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Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Section: The Effects Of Artemisinin and Its Derivatives On Cellular Signaling Pathwaysmentioning

confidence: 99%

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Qiu

Liu

et al. 2021

Front. Immunol.

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“…STAT3 signaling is enhanced by IL-6 and IL-21, which promotes the expression of Bcl-6. Previous studies have demonstrated that STAT3 is involved in the pathogenesis of SLE; indeed, a STAT3 genetic de ciency, STAT3 inhibitors, and agents that inhibit expression of STAT3 all provide a protective effect against SLE [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Niclosamide Suppresses the Expansion of Follicular Helper T Cells and Alleviates Disease Severity in Two Murine Models of Lupus via STAT3

Jang

Lee

Hong

et al. 2020

Preprint

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Background. Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (TFH) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to TFH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether Niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of TFH cells in two murine models of lupus.Methods. 10-week-old MRL/lpr mice were orally administered with 100 mg/kg of Niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of Niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization.Results. Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, Niclosamide inhibited the proportion of TFH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of TFH-like cells and expression of associated genes in vitro.Conclusions. Niclosamide exerted therapeutic effects on murine lupus models by suppressing TFH cells and plasma cells through STAT3 inhibition.

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“…Some biological extracts or newly synthesized substances might alleviate LN by targeting JAK/STAT pathways. For example, artesunate (an anti-malarial drug) ameliorated the LN symptoms by inhibiting JAK2/STAT3 [ 76 ]. Synthetic triterpenoid CDDO-Me suppressed the onset and development of LN, partly by inhibiting JAK1/STAT3 [ 77 ].…”

Section: The Stat Signaling Pathways and Renal Diseasesmentioning

confidence: 99%

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

Gai

Zhu

Zhang

et al. 2021

Cells

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Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.

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Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2–STAT3 signaling pathway

Cited by 41 publications

References 33 publications

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Immunoregulation by Artemisinin and Its Derivatives: A New Role for Old Antimalarial Drugs

Niclosamide Suppresses the Expansion of Follicular Helper T Cells and Alleviates Disease Severity in Two Murine Models of Lupus via STAT3

Targeting Canonical and Non-Canonical STAT Signaling Pathways in Renal Diseases

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