Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Bartels, Marije; Govers, Anita M A P; Fleskens, Veerle; Lourenço, Ana Rita; Pals, Cornelieke E.G.M.; Vervoort, Stephin J.; Gent, Rogier van; Brenkman, Arjan B.; Bierings, Marc; Ackerman, Steven J.; Loosdregt, Jorg van; Coffer, Paul J.

doi:10.1182/blood-2013-12-543850

Blood

2015

DOI: 10.1182/blood-2013-12-543850

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Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Marije Bartels

Anita M A P Govers

Veerle Fleskens

et al.

Abstract: Key Points C/EBPε acetylation regulates C/EBPε transcriptional activity. C/EBPε acetylation is required for neutrophil differentiation and the formation of neutrophil-specific granules.

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Cited by 33 publications

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“…One conclusion could be that acetylation at these lysines is selectively important for differentiation along either the neutrophil or eosinophil lineages (see figure). 1 A limitation of the current study is that the conclusions are based on in vitro experiments. Future studies in a mouse model could provide more definitive evidence that acetylation of C/EBPe is essential during granulopoiesis in vivo.…”

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confidence: 91%

“…6 There was an intriguing correlation between CRP concentrations in 14 different healthy sera and antibody-mediated phagocytic activity against platelets. 1 In addition, purified CRP was clearly shown to enhance antibodymediated phagocytic responses against platelets, and CRP depletion and repletion experiments corresponded to IgG-mediated phagocytic activity against platelets. Several experiments were performed to elucidate the working mechanism of CRP in IgG-mediated targeting of platelets.…”

mentioning

confidence: 92%

“…C/EBPe 32/30 activates transcription, C/EBPe 27 represses transcription, and C/EBPe 14 acts as a dominant negative. 1 The contribution of these different isoforms toward granulocytic differentiation remains largely unknown as is the importance of posttranslational modifications. Phosphorylation, sumoylation, and acetylation modulate the transcriptional activities of several C/EBP family members.…”

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confidence: 99%

“…7 Acetylation of C/EBPb is functionally linked to transcriptional activity, but its impact on granulopoiesis is unknown. 1 Phosphorylation of C/EBPe on threonine 75, which is located in the transactivation domain, leads to increased DNA binding and transcriptional activity, and sumolyation of a lysine residue 121 (K121) within repression domain I enhances transcriptional activation by C/EBPe.…”

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confidence: 99%

“…Kapur et al describe a series of elegant studies in which a serum factor was found to enhance IgG-mediated responses (respiratory burst and phagocytosis) against platelets. 1 The involvement of the complement cascade was excluded, and the factor was found to be present in healthy sera and appeared to be acting against platelets in a calcium-dependent manner. As such, CRP was convincingly identified as the serum factor that enhanced IgG-mediated phagocytosis of platelets.…”

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confidence: 99%

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The end of the line for neutrophils

Gombart

2015

Blood

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confidence: 91%

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confidence: 92%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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The end of the line for neutrophils

Gombart

2015

Blood

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Annexin A1 Is a Physiological Modulator of Neutrophil Maturation and Recirculation Acting on the CXCR4/CXCL12 Pathway

et al. 2016

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Neutrophil production and traffic in the body compartments is finely controlled, and the strong evidences support the role of CXCL12/CXCR4 pathway on neutrophil trafficking to and from the bone marrow (BM). We recently showed that the glucocorticoid-regulated protein, Annexin A1 (AnxA1) modulates neutrophil homeostasis and here we address the effects of AnxA1 on steady-state neutrophil maturation and trafficking. For this purpose, AnxA1(-/-) and Balb/C wild-type mice (WT) were donors of BM granulocytes and mesenchymal stem cells and blood neutrophils. In vivo treatments with the pharmacological AnxA1 mimetic peptide (Ac2-26) or the formyl peptide receptor (FPR) antagonist (Boc-2) were used to elucidate the pathway of AnxA1 action, and with the cytosolic glucocorticoid antagonist receptor RU 38486. Accelerated maturation of BM granulocytes was detected in AnxA1(-/-) and Boc2-treated WT mice, and was reversed by treatment with Ac2-26 in AnxA1(-/-) mice. AnxA1 and FPR2 were constitutively expressed in bone marrow granulocytes, and their expressions were reduced by treatment with RU38486. Higher numbers of CXCR4(+) neutrophils were detected in the circulation of AnxA1(-/-) or Boc2-treated WT mice, and values were rescued in Ac2-26-treated AnxA1(-/-) mice. Although circulating neutrophils of AnxA1(-/-) animals were CXCR4(+) , they presented reduced CXCL12-induced chemotaxis. Moreover, levels of CXCL12 were reduced in the bone marrow perfusate and in the mesenchymal stem cell supernatant from AnxA1(-/-) mice, and in vivo and in vitro CXCL12 expression was re-established after Ac2-26 treatment. Collectively, these data highlight AnxA1 as a novel determinant of neutrophil maturation and the mechanisms behind blood neutrophil homing to BM via the CXCL12/CXCR4 pathway. J. Cell. Physiol. 231: 2418-2427, 2016. © 2016 Wiley Periodicals, Inc.

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Neutrophil progenitor populations of rhesus macaques

Weisgrau

Vosler

Pomplun

et al. 2018

Journal of Leukocyte Biology

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Captive-bred rhesus macaques of Indian origin represent one of the most important large animal models for infectious disease, solid organ transplantation and stem cell research. There is a dearth of information defining hematopoietic development, including neutrophil leukocyte differentiation in this species using multicolor flow cytometry. In the current study we sought to identify cell surface markers that delineate neutrophil progenitor populations with characteristic immunophenotypes. We defined four different post-mitotic populations based on their CD11b and CD87 expression pattern, and further refined their immunophenotypes using CD32, CD64, lactoferrin and myeloperoxidase as antigenic markers. The four subsets contained myelocyte, metamyelocyte, band, and segmented neutrophil populations. We compared our flow cytometry-based classification with the classical nuclear morphology-based classification. We found overlap of immunological phenotype between populations of different nuclear morphology and identified phenotypically different subsets within populations of similar nuclear morphology. We assessed the responsiveness of these populations to stimulatory signals such as LPS, fMPL or PMA, and demonstrated significant differences between human and rhesus macaque neutrophil progenitors. In this study we provided evidence for species-specific features of granulopoiesis that ultimately manifested in the divergent immunophenotypes of the fully differentiated segmented neutrophils of humans and rhesus macaques. Additionally, we found functional markers that can be used to accurately quantify neutrophil progenitors by flow cytometry. While these markers do not coincide with the classical nuclear-morphology-based grading they enable us to perform functional studies monitoring immunophenotypic markers.

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Acetylation of C/EBPε is a prerequisite for terminal neutrophil differentiation

Abstract: Key Points C/EBPε acetylation regulates C/EBPε transcriptional activity. C/EBPε acetylation is required for neutrophil differentiation and the formation of neutrophil-specific granules.

Cited by 33 publications

References 47 publications

The end of the line for neutrophils

The end of the line for neutrophils

Annexin A1 Is a Physiological Modulator of Neutrophil Maturation and Recirculation Acting on the CXCR4/CXCL12 Pathway

Neutrophil progenitor populations of rhesus macaques

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