Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

Niño, Diego F.; Cauvi, David M.; Maio, Antonio De

doi:10.1097/shk.0000000000000169

Cited by 11 publications

(8 citation statements)

References 35 publications

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“…Additionally, others have shown that ITA affects the glycosylation and trafficking of other cell surface molecules including CD14 and Fc receptors; however, the relevant cellular target responsible for ITA's effects on receptor trafficking remains unknown (36,37). Recently, others have reported that ITA inhibits enterovirus replication by binding to oxysterol binding protein (OSBP) and that ITA modulates mTORC1 activity by inhibiting the mitochondrial protein voltagedependent anion channel 1 (VDAC1) (38,39).…”

Section: Discussionmentioning

confidence: 99%

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Bollong

Yang

Vergani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.

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Section: Discussionmentioning

confidence: 99%

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Bollong

Yang

Vergani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were then washed and at least 100,000 live cells per sample were analyzed using a BD Accuri C6 Flow Cytometer (BD Biosciences). Flow cytometry data analysis was performed using FlowJo software (FlowJo) as previously described (18). …”

Section: Methodsmentioning

confidence: 99%

Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells

Niño¹,

Sodhi²,

Egan³

et al. 2017

Shock

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Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4+Th17 (Th17) cells and reduced anti-inflammatory Foxp3+ regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs–Lgr5+cells) within the crypts of Lieberkühn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of intestinal stem cells. Utilizing both in vivo and in vitro strategies we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine.

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“…Our recent observations also indicated that FcγR expression levels were altered by inhibition of cholesterol biosynthesis. 38 The promoter region of this gene did not display any lipid-driving element that could predict a regulation at the transcriptional level, although we cannot discount the involvement of transcription enhancers. Additionally, changes in mRNA stability may be involved in regulating changes in FcγR expression levels after exposure to different cholesterol contents.…”

Section: Discussionmentioning

confidence: 73%

“…36,37 Moreover, we have recently found that incubation of Mϕs with itraconazole, another inhibitor of cholesterol synthesis, affected phagocytosis. 38 The differences in phagocytic function between suspension and attached Mϕs were proportional to the levels of Fc receptors in these cells. The mechanism for the modulation of FcγR expression by cholesterol is unknown.…”

Section: Discussionmentioning

confidence: 96%

Changes in macrophage function modulated by the lipid environment

et al. 2016

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Macrophages (Mϕs) play a critical role in the defense against pathogens, orchestrating the inflammatory response during injury and maintaining tissue homeostasis. During these processes, macrophages encounter a variety of environmental conditions that are likely to change their gene expression pattern, which modulates their function. In this study, we found that murine Mϕs displayed two different subpopulations characterized by differences in morphologies, expression of surface markers and phagocytic capacity under non-stimulated conditions. These two subpopulations could be recapitulated by changes in the culture conditions. Thus, Mϕs grown in suspension in the presence of serum were highly phagocytic, whereas subtraction of serum resulted in rapid attachment and reduced phagocytic activity. The difference in phagocytosis between these subpopulations was correlated with the expression levels of FcγR. These two cell subpopulations also differed in their responses to LPS and the expression of surface markers, including CD14, CD86, scavenger receptor A1, TLR4 and low-density lipoprotein receptor. Moreover, we found that the lipid/cholesterol content in the culture medium mediated the differences between these two cell subpopulations. Thus, we described a mechanism that modulates Mϕ function depending on the exposure to lipids within their surrounding microenvironment.

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Itraconazole, a Commonly Used Antifungal, Inhibits Fcγ Receptor–Mediated Phagocytosis

Cited by 11 publications

References 35 publications

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells

Changes in macrophage function modulated by the lipid environment

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