Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells

Sasaki, Haruka; Kurotaki, Daisuke; Osato, Naoki; Sato, Hideaki; Sasaki, Izumi; Koizumi, Shin; Wang, Hongsheng; Kaneda, Chika; Nishiyama, Akira; Kaisho, Tsuneyasu; Aburatani, Hiroyuki; Morse, Herbert C.; Ozato, Keiko; Tamura, Tomohide

doi:10.1182/blood-2014-02-557983

Cited by 59 publications

(51 citation statements)

References 50 publications

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“…Moreover, the expression of Gata1, a transcription factor gene crucial for eosinophil development, is reduced in Irf8 −/− EoPs [49]. More recently, we found that Irf8 −/− mice are basophil deficient [17]. Basophils are the least common granulocytes circulating in peripheral blood, but their critical roles in Th2-type immunity and allergic disorders have been recently clarified.…”

Section: Regulation Of Eosinophil Basophil and Mast Cell Developmenmentioning

confidence: 85%

“…We found that Gata2, which encodes a transcription factor known to promote basophil differentiation, is induced by IRF8 in GPs and crucially acts downstream of IRF8 (Fig. 3) [17].…”

Section: Regulation Of Eosinophil Basophil and Mast Cell Developmenmentioning

confidence: 99%

“…Indeed, the partial inhibition of C/EBP activity in Irf8 −/− hematopoietic progenitors alleviates in vivo neutrophil overproduction. A more recent study from our laboratory suggests that another mechanism in GPs also exists [17], in which the transcription factor GATA2 acts downstream of IRF8 in GPs to limit their neutrophil differentiation potential (see the next section).…”

Section: Regulation Of Neutrophil Development By Irf8mentioning

confidence: 99%

“…GPs is biased toward neutrophils [17]. Hence, Irf8 −/− ALPs and GPs are also likely to contribute to neutrophilia.…”

Section: Regulation Of Neutrophil Development By Irf8mentioning

confidence: 99%

“…Monocytes . Granulocyte progenitors (GPs) [16] are IRF8 lo , whereas their progenies (i.e., granulocytes such as neutrophils, eosinophils, and basophils) and mast cells do not express IRF8 [17] (Fig. 3).…”

Section: Irf8gfp/wtmentioning

confidence: 99%

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Regulation of myelopoiesis by the transcription factor IRF8

2015

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Section: Regulation Of Eosinophil Basophil and Mast Cell Developmenmentioning

confidence: 85%

“…We found that Gata2, which encodes a transcription factor known to promote basophil differentiation, is induced by IRF8 in GPs and crucially acts downstream of IRF8 (Fig. 3) [17].…”

Section: Regulation Of Eosinophil Basophil and Mast Cell Developmenmentioning

confidence: 99%

Section: Regulation Of Neutrophil Development By Irf8mentioning

confidence: 99%

“…GPs is biased toward neutrophils [17]. Hence, Irf8 −/− ALPs and GPs are also likely to contribute to neutrophilia.…”

Section: Regulation Of Neutrophil Development By Irf8mentioning

confidence: 99%

Section: Irf8gfp/wtmentioning

confidence: 99%

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Regulation of myelopoiesis by the transcription factor IRF8

2015

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IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Zhang

Qiu

et al. 2021

Advanced Science

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IRF8 is a key regulator of innate immunity receptor signaling and plays diverse functions in the development of hematopoietic cells. The effects of IRF8 on hematopoietic stem cells (HSCs) are still unknown. Here, it is demonstrated that IRF8 deficiency results in a decreased number of long-term HSCs (LT-HSCs) in mice. However, the repopulation capacity of individual HSCs is significantly increased. Transcriptomic analysis shows that IFN-and IFNsignaling is downregulated in IRF8-deficient HSCs, while their response to proinflammatory cytokines is unchanged ex vivo. Further tests show that Irf8 −/− HSCs can not respond to CpG, an agonist of Toll-like receptor 9 (TLR9) in mice, while long-term CpG stimulation increases wild-type HSC abundance and decreases their bone marrow colony-forming capacity. Mechanistically, as the primary producer of proinflammatory cytokines in response to CpG stimulation, dendritic cells has a blocked TLR9 signaling due to developmental defect in Irf8 −/− mice. Macrophages remain functionally intact but severely reduce in Irf8 −/− mice. In NK cells, IRF8 directly regulates the expression of Tlr9 and its deficiency leads to no increased IFN production upon CpG stimulation. These results indicate that IRF8 regulates HSCs, at least in part, through controlling TLR9 signaling in diverse innate immune cells.

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Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis

Izawa

Kurotaki

Nomura

et al. 2019

Journal of Bone and Mineral Research

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Receptor activator of nuclear factor kB ligand (RANKL) induces osteoclast (OC) differentiation from bone marrow-derived macrophages (BMMs). The transcription factors nuclear factor of activated T cells 1 (NFATc1) and interferon regulatory factor (IRF) 8 play positive and negative roles, respectively, in this process. However, genomewide mapping of the active cis-regulatory elements regulating OC differentiation has not been performed, and little is known about the global landscape of OC-specific gene regulation. We used chromatin immunoprecipitation and formaldehyde-assisted isolation of regulatory elements followed by sequencing to show that PU.1 transcription factor binding motifs were overrepresented at active cis-regulatory regions in both murine BMMs and OCs, while IRF and NFAT binding motifs were selectively enriched at these regions in BMMs and OCs, respectively. We also found that RANKL induced the downregulation of Irf8 and upregulation of Nfatc1 expression, which was associated with dramatic alterations in histone modification. BMM-specific PU.1 binding sites were observed to overlap with IRF8 binding sites in BMMs, and this also occurred for OC-specific PU.1 binding sites and NFATc1 binding sites in OCs. The expression of genes with IRF8 peaks within BMMspecific PU.1 binding sites was significantly higher in BMMs than in OCs, while that of genes with NFATc1 peaks within OC-specific PU.1 binding sites was significantly higher in OCs than in BMMs. Our results suggest that PU.1 switches its transcription partner from IRF8 to NFATc1 and alters the binding regions during RANKL-induced osteoclastogenesis, which is associated with changes in epigenetic profiles and the control of cell type-specific gene expression.

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Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells

Abstract: Key Points IRF8 promotes Gata2 expression in GPs, thereby playing a key role in the development of basophils and mast cells.

Cited by 59 publications

References 50 publications

Regulation of myelopoiesis by the transcription factor IRF8

Regulation of myelopoiesis by the transcription factor IRF8

IRF8 Impacts Self‐Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis

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