Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells

Eskandarpour, Malihe; Alexander, Randell; Adamson, Peter; Calder, Virginia L.

doi:10.4049/jimmunol.1600735

Cited by 22 publications

(32 citation statements)

References 63 publications

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“…The key finding was that BET inhibition markedly upregulated forkhead box P3 (FoxP3 + ) expression accompanied by lowered pathogenicity in vivo, suggesting that BET inhibition may switch retinal CD4 + T cell polarity from a T H 17 to T reg phenotype. Thus, it may represent a viable therapeutic entry point for inflammatory and autoimmune disorders which primarily depend upon the T H 17/Treg axis for disease resolution [ 23 ].…”

Section: Ccr6–ccl20 Inhibition In Multiple Organ Systemsmentioning

confidence: 99%

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Ranasinghe

Eri

2018

Medicina

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Prototypical functions of the chemokine receptor CCR6 include immune regulation by maneuvering cell chemotaxis and selective delimiting of the pro-inflammatory TH17 and regulatory Treg subsets during chronic or acute systemic inflammation. Inhibition of CCR6 is proposed to attenuate disease symptoms and promote recuperation of multiple inflammatory and autoimmune disorders. Prescription medicines with pharmacodynamics involving the inhibition of the chemokine axis CCR6–CCL20 are very limited. The development of such therapeutics is still at an early experimental stage and has mostly involved the utilization of pre-clinical models and neutralizing mono or polyclonal antibodies against either partner (CCR6 or CCL20). Other methods include the constitutive use of small molecules as peptide inhibitors or small interfering ribonucleic acid (siRNA) to interfere with transcription at the nuclear level. In our review, we aim to introduce the wide array of potential CCR6–CCL20 inhibitors with an emphasis on attendant immune-modulator capacity that have been tested in the research field to date and are immensely promising compounds as forerunners of future curatives. Sixteen different tractable inhibitors of the CCR6–CCL20 duo have been identified as possessing high medicinal potential by drug developers worldwide to treat autoimmune and inflammatory diseases as shown in Figure 1. A multitude of antibody preparations are already available in the current pharmaceutical market as patented treatments for diseases in which the CCR6–CCL20 axis is operative, yet they must be used only as supplements with existing routinely prescribed medication as they collectively produce adverse side effects. Novel inhibitors are needed to evaluate this invaluable therapeutic target which holds much promise in the research and development of complaisant remedies for inflammatory diseases.

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Section: Ccr6–ccl20 Inhibition In Multiple Organ Systemsmentioning

confidence: 99%

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Ranasinghe

Eri

2018

Medicina

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“…Our group previously reported using an epigenetic target in EAU, in which it could also inhibit interphotoreceptor retinoid‐binding protein (IRBP)‐specific Th17/Th1 cells in vitro. The data suggested that blocking plasticity of effector T cells may be controlled by chromatin regulators [26]. In our current study, while dexamethasone effectively downregulated EAU severity scores via a Th1 cell reduction, the disease itself was not completely suppressed.…”

Section: Discussionmentioning

confidence: 46%

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

et al. 2020

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Immunopathogenic roles for both Th1 (CD4 + IFN-γ +) and Th17 (CD4 + IL-17A +) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4 + T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy.

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“…These data suggest that BET inhibition could exert beneficial effects on renal damage by modulating the Th17 immune response ( Figure 3 ). There are studies about the effect of BET pharmacological inhibition on different pathologies associated with Th17 response, results that support these data, as described in colitis (Cheung et al, 2017), experimental autoimmune encephalomyelitis (Jahagirdar et al, 2017a), retinal inflammatory disease (Eskandarpour et al, 2017), and asthma (Nadeem et al, 2018).…”

Section: Introductionmentioning

confidence: 70%

Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases

et al. 2019

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Epigenetic mechanisms, especially DNA methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. The bromodomain and extraterminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. Experimental data have demonstrated the involvement of some BET proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. Selective bromodomain inhibitors are epigenetic drugs that block the interaction between BET proteins and acetylated proteins, thus exerting beneficial effects. Recent data have described the beneficial effect of BET inhibition on experimental renal diseases. Emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (CKD). Several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in CKD patients. Here, we review how targeting bromodomains in BET proteins may regulate essential processes involved in renal diseases and in associated complications found in CKD patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against BET proteins for CKD treatment and associated risks.

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Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells

Cited by 22 publications

References 63 publications

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases

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Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells

Cited by 22 publications

References 63 publications

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Functionally distinct IFN‐γ+IL‐17A+ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response

Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases

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Functionally distinct IFN‐γ⁺IL‐17A⁺ Th cells in experimental autoimmune uveitis: T‐cell heterogeneity, migration, and steroid response