Inhibition of the chemokine signal regulator FROUNT by disulfiram ameliorates crescentic glomerulonephritis

Toda, Etsuko; Sawada, Anri; Takeuchi, Kazuhiro; Wakamatsu, Kazumasa; Ishikawa, Arimi; Kuwahara, Naomi; Sawa, Yurika; Hatanaka, Saeko; Kokubo, Kana; Makino, Kosho; Takahashi, Hideyo; Endo, Yuichi; Κunugi, Shinobu; Terasaki, Mika; Terasaki, Yasuhiro; Matsushima, Kouji; Terashima, Yuya; Shimizu, Akira

doi:10.1016/j.kint.2022.07.031

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…The length of macrophages in the DSF group was significantly shorter compared to the Vehicle group. In a previous study, we reported that macrophages infiltrating glomeruli were smaller in size in the group treated orally with DSF in a rat model of anti-GBM glomerulonephritis [21]. The results of this experiment also show a similar reduction in the size of infiltrating macrophages, which indirectly suggests that DSF may inhibit macrophage pseudopodia formation by inhibiting FROUNT.…”

Section: Discussionsupporting

confidence: 74%

“…In this study, we enumerated pan-macrophages (including both M1 and M2 macrophages); thus, the effect of DSF eye drops on M2 macrophages is unknown. Previous DSF reports on glomeruli have shown that M2 macrophages were reduced, but fibrosis was suppressed [21]. M2 macrophages should also be evaluated in a corneal alkali burn model in the future.…”

Section: Discussionmentioning

confidence: 90%

“…In recent years, it has attracted attention for its many reported inhibitory effects on cancer and inflammation [18][19][20]. Our group has found inhibitory effects on cancer-associated macrophages and macrophages in glomerulonephritis in relation to FROUNT inhibition [17,21]. In the ophthalmology field, DSF eye drops have been studied in a rat model of uveitis but there are no reports regarding corneal scarring and angiogenesis [22].…”

Section: Introductionmentioning

confidence: 99%

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Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model

Ikebukuro

Arima

Kasamatsu

et al. 2023

IJMS

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FROUNT is an intracellular protein that promotes pseudopodia formation by binding to the chemokine receptors CCR2 and CCR5 on macrophages. Recently, disulfiram (DSF), a drug treatment for alcoholism, was found to have FROUNT inhibitory activity. In this study, we investigated the effect of DSF eye drops in a rat corneal alkali burn model. After alkali burn, 0.5% DSF eye drops (DSF group) and vehicle eye drops (Vehicle group) were administered twice daily. Immunohistochemical observations and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed at 6 h and 1, 4, and 7 days after alkali burn. Results showed a significant decrease in macrophage accumulation in the cornea in the DSF group, but no difference in neutrophils. RT-PCR showed decreased expression of macrophage-associated cytokines in the DSF group. Corneal scarring and neovascularization were also suppressed in the DSF group. Low-vacuum scanning electron microscopy imaging showed that macrophage length was significantly shorter in the DSF group, reflecting the reduced extension of pseudopodia. These results suggest that DSF inhibited macrophage infiltration by suppressing macrophage pseudopodia formation.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model

Ikebukuro

Arima

Kasamatsu

et al. 2023

IJMS

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“…Our group reported that DSF inhibits the expression of the cytoplasmic protein FROUNT in macrophages, suppressing their migration and activation [ 12 , 13 ], whose effect may have decreased the proportion of CD68 + cells in the grafts. We did not observe a decrease in CCL2 levels in the serum or lung tissues in this study, and this is consistent with the fact that DSF has been shown to inhibit intracellular signaling between FROUNT and chemokine receptors (CCR2 or CCR5) on macrophages [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts

Yoshiyasu,

Matsuki,

Sato

et al. 2024

Transpl Int

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Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280–300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

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“…Franchi, S et al [ 65 ] examined the effects of DSF, naltrexone and gamma-hydroxybutyric acid on the immune response in alcoholics and showed increased concentrations of IL-1, IL-4, IL-2 and IFN in the DSF group. In glomerulonephritis, DSF has been shown to attenuate macrophage activation by downregulating the expression of inflammatory cytokines and chemokines, such as TNF-α, CCL2, and CXCL9, as well as by decreasing the expression of CD86 and MHC class II in monocytes and macrophages [ 66 ]. The studies conducted thus far demonstrate that DSF is capable of modulating the secretion and release of cytokines.…”

Section: Disulfiram Regulates Immune Cell Functionmentioning

confidence: 99%

The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics

et al. 2023

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More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems.

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Inhibition of the chemokine signal regulator FROUNT by disulfiram ameliorates crescentic glomerulonephritis

Cited by 7 publications

References 46 publications

Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model

Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model

Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts

The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics

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