Bcl‐2 Antagonists Kill Plasmacytoid Dendritic Cells From Lupus‐Prone Mice and Dampen Interferon‐α Production

Zhan, Yifan; Carrington, Emma M.; Ko, Hyun-Ja; Vikström, Ingela B; Oon, Shereen; Zhang, Jianguo; Vremec, David; Brady, Jamie L.; Bouillet, Philippe; Wu, Li; Huang, David C.S.; Wicks, Ian P.; Morand, Eric Francis; Strasser, Andreas; Lew, Andrew M.

doi:10.1002/art.38966

Cited by 43 publications

(60 citation statements)

References 59 publications

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“…This finding was not surprising given the dysregulation of IFN in human systemic lupus erythematosus (SLE) (41,42) and in NZW/B lupus model mice (ref. 43 and references therein). Because recent studies have reported Treg modulation by IFN (reviewed in ref.…”

Section: Resultsmentioning

confidence: 99%

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Dépis

Kwon

Mathis

et al. 2016

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

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Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.Treg homeostasis | FoxP3 stability | immunoregulation | inbred mice

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Section: Resultsmentioning

confidence: 99%

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Dépis

Kwon

Mathis

et al. 2016

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

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“…S2H). Conversely, ABT-199 significantly reduces IFN-α production by pDCs, including pDCs from lupus-prone (NZB/NZW F1) mice (34).…”

Section: Discussionmentioning

confidence: 96%

“…This differential dependence on BCL-2 advocates the use of BCL-2 selective antagonist BH3 mimetic drugs for treating pDC-associated diseases (34). Refined understanding of how the survival of the distinct DC subsets is regulated is therefore expected to provide valuable insight into the pathogenesis of inflammatory diseases and guide the development of effective therapeutic interventions for such diseases.…”

Section: Discussionmentioning

confidence: 99%

Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

Carrington

Zhang

Sutherland

et al. 2015

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

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Dendritic cells (DCs) are heterogeneous, comprising subsets with functional specializations that play distinct roles in immunity as well as immunopathology. We investigated the molecular control of cell survival of two main DC subsets: plasmacytoid DCs (pDCs) and conventional DCs (cDCs) and their dependence on individual antiapoptotic BCL-2 family members. Compared with cDCs, pDCs had higher expression of BCL-2, lower A1, and similar levels of MCL-1 and BCL-XL. Transgenic overexpression of BCL-2 increased the pDC pool size in vivo with only minor impact on cDCs. With a view to immune intervention, we tested BCL-2 inhibitors and found that ABT-199 (the BCL-2 specific inhibitor) selectively killed pDCs but not cDCs. Conversely, genetic knockdown of A1 profoundly reduced the proportion of cDCs but not pDCs. We also found that conditional ablation of MCL-1 significantly reduced the size of both DC populations in mice and impeded DC-mediated immune responses. Thus, we revealed that the two DC types have different cell survival requirements. The molecular basis of survival of different DC subsets thus advocates the antagonism of selective BCL-2 family members for treating diseases pertaining to distinct DC subsets.apoptosis | dendritic cells | BH3-mimetic

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“…A study evaluating the dependence of plasmacytoid dendritic cells (pDCs) and conventional DCs (cDCs) on antiapoptotic proteins revealed that pDCs had higher levels of BCL-2 compared with cDCs, and were selectively killed when cultured in vitro with venetoclax, highlighting their dependence on BCL-2 for survival (124). Using a similar chemical parsing approach, the BCL-2 inhibitors venetoclax and ABT-737 were found to selectively kill mouse and human pDCs but not cDCs, and synergized with glucocorticoids to kill activated pDCs (125). These findings indicated that BCL-2 antagonists may be attractive candidates for treating pDC-associated diseases such as BPDCN.…”

Section: Future Considerations and Conclusionmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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Bcl‐2 Antagonists Kill Plasmacytoid Dendritic Cells From Lupus‐Prone Mice and Dampen Interferon‐α Production

Cited by 43 publications

References 59 publications

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

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Bcl‐2 Antagonists Kill Plasmacytoid Dendritic Cells From Lupus‐Prone Mice and Dampen Interferon‐α Production

Cited by 43 publications

References 59 publications

Unstable FoxP3 + T regulatory cells in NZW mice

Unstable FoxP3 + T regulatory cells in NZW mice

Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

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Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Unstable FoxP3 ⁺ T regulatory cells in NZW mice