Cutting Edge: Krüppel-like Factor 2 Is Required for Phenotypic Maintenance but Not Development of B1 B Cells

Hart, Geoffrey T.; Peery, Stephen L.; Hamilton, Sara E.; Jameson, Stephen C.

doi:10.4049/jimmunol.1201439

Cited by 10 publications

(13 citation statements)

References 28 publications

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“…Migration of these cells has been described to occur in waves [14,15]. However, during the second week of life about 20% of B cells were observed in peritoneal cavities [16]. Our data suggests that the migration of B cells into the peritoneal cavity occurs during the first days after birth, when local macrophages express sufficient amounts of homing factors like CXCL13 [13], which was not expressed at the investigated age (<24 h).…”

Section: Discussionmentioning

confidence: 82%

Distinct phenotypic features of neonatal murine macrophages

et al. 2014

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Neonates rely on their innate immune system. Resident tissue macrophages are considered to be initiators and regulators of the innate immune response and thus, appear to be especially important to neonates. We hypothesized that the phenotype and function of neonatal tissue macrophages differ from their adult counterparts. Peritoneal macrophages from neonatal (<24 h) and adult (6 weeks old) C57BL/6J mice were isolated and analyzed by high-content chipcytometry. After stimulation for 6 h with LPS (0, 1, 10, 100 ng/mL), macrophage transcriptome was analyzed by microarray and cytokine release was measured using multiparametric bead assays. Antigen presenting capacity was compared by T-cell stimulation assays. We observed that neonatal murine peritoneal macrophages are characterized by selective lack of expression of F4/80, MHC class II, and costimulatory molecules (CD80, CD86). Furthermore, we found differences in the transcriptome between neonatal and adult macrophages, unstimulated and after LPS stimulation. Although neonatal macrophages showed a significantly increased secretion of proinflammatory cytokines upon LPS stimulation, their potential to induce T-cell proliferation was significantly reduced. In conclusion, we observed a distinct phenotype of the neonatal macrophage population. The specific functions of this macrophage population could help to understand the excessive inflammatory reactions observed in the very young.Keywords: Immune responses r Macrophages r Neonate immunity r Toll-like receptors (TLRs) Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNeonates and in particular preterm infants are extremely vulnerable to states of inflammation [1]. They have an increased susceptibility to microbial infections with an enhanced morbidity and Correspondence: Mr. Thomas Winterberg e-mail: Winterberg.thomas@mh-hannover.de mortality [2]. Sepsis, pneumonia, and gastrointestinal disorders such as necrotizing enterocolitis are a common threat to patients in neonatal intensive care. The first days of life represent a period of transition of the immune system: The protection of the fetus by the maternal immune system and the sterile environment are lost and the newborn has to cope with the outside world and its multiple foreign antigens. Although maternal antibodies help the neonate in the first weeks, it has to develop its own adaptive immune capacities during infancy [2]. In the neonatal period, monocytes and [6][7][8][9]. Until now, neonatal monocytes and macrophages have been described as immature or dormant myeloid cells. However, these studies are based on peripheral blood monocytes or CBMs, which further differentiate into macrophages ex vivo. Little is known about tissue macrophages in neonates, due to technical difficulties of their isolation and evaluation, but a recent study demonstrated their unique function during heart tissue regeneration [10].It has been shown that the heterogeneous murine macrophage populations are orig...

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Section: Discussionmentioning

confidence: 82%

Distinct phenotypic features of neonatal murine macrophages

et al. 2014

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“…3a ). Among these putative KDM3A targets, a gene of particular interest is KLF2 , a key molecule in maintenance of B cell and plasma cell phenotype and function 21 22 23 24 . Another relevant gene is IRF4 , given its known crucial role in MM cell survival 29 .…”

Section: Resultsmentioning

confidence: 99%

“…KLF2, a nuclear DNA-binding transcription factor of the Krüppel zinc-finger family, is involved in various biological processes including blood vessel and lung formation, as well as T-cell homeostasis 18 . KLF2 is also expressed in B cells 19 20 , and absence of KLF2 in B-cell compartment causes abnormalities in B-cell subset identity, cellular trafficking and humoral immunity 21 22 23 24 . Thus, KLF2 plays a crucial role in maintaining homeostasis of B cells and plasma cells; however, the functional significance of KLF2 in MM remains to be defined.…”

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confidence: 99%

The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

et al. 2016

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KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A–KLF2–IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A–KLF2–IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

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“…Krüppel‐like transcription factor (KLF)s are involved in regulation of terminal differentiation of several immune cells. Lung KLF (LKLF) or KLF2 plays a significant regulatory role in haematopoietic cell biology including cell quiescence, cell proliferation, differentiation and survival . KLF2 also regulates myeloid cell activation and function .…”

Section: Introductionmentioning

confidence: 99%

“…Lung KLF (LKLF) or KLF2 plays a significant regulatory role in haematopoietic cell biology including cell quiescence, cell proliferation, differentiation and survival. 9,10 KLF2 also regulates myeloid cell activation and function. 11 During inflammation, KLF2 acts as a potent inhibitor of transcription factors like NF-κB and AP1, as well as of hypoxia-related HIF-1α protein.…”

mentioning

confidence: 99%

Induction of Krüppel‐like factor 2 reduces K/BxN serum‐induced arthritis

Das

Laha

Sugita

et al. 2018

J Cellular Molecular Medi

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Krüppel‐like factor 2 (KLF2) critically regulates activation and function of monocyte, which plays important pathogenic role in progressive joint destruction in rheumatoid arthritis (RA). It is yet to be established the molecular basis of KLF2‐mediated regulation of monocytes in RA pathogenesis. Herein, we show that a class of compound, HDAC inhibitors (HDACi) induced KLF2 expression in monocytes both in vitro and in vivo. KLF2 level was also elevated in tissues, such as bone marrow, spleen and thymus in mice after infusion of HDACi. Importantly, HDACi significantly reduced osteoclastic differentiation of monocytes with the up‐regulation of KLF2 and concomitant down‐regulation of matrixmetalloproteinases both in the expression level as well as in the protein level. In addition, HDACi reduced K/BxN serum‐induced arthritic inflammation and joint destruction in mice in a dose‐dependent manner. Finally, co‐immunoprecipitation and overexpression studies confirmed that KLF2 directly interacts with HDAC4 molecule in cells. These findings provide mechanistic evidence of KLF2‐mediated regulation of K/BxN serum‐induced arthritic inflammation.

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Cutting Edge: Krüppel-like Factor 2 Is Required for Phenotypic Maintenance but Not Development of B1 B Cells

Cited by 10 publications

References 28 publications

Distinct phenotypic features of neonatal murine macrophages

Distinct phenotypic features of neonatal murine macrophages

The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

Induction of Krüppel‐like factor 2 reduces K/BxN serum‐induced arthritis

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