Demand-adapted regulation of early hematopoiesis in infection and inflammation

Takizawa, Hajime; Boettcher, Steffen; Manz, Markus G.

doi:10.1182/blood-2011-12-380113

Cited by 370 publications

(351 citation statements)

References 126 publications

(127 reference statements)

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“…This is associated with increased committed myeloid progenitors and myeloid cells and decreased B cells in the BM along with increased circulating neutrophils, IL-6, and G-CSF in Tle1-deficient mice. It is similar to the effects seen with dysregulation of inflammatory pathways and infections (27) and the increase in G-CSF and granulopoiesis seen with constitutive activation of NF-κB in IκBa-deficient mice (28). In addition, in vitro overexpression of Tle1 in monocyte/macrophage cell lines blocks LPS-induced NF-κB nuclear translocation and phosphorylation.…”

Section: Discussionsupporting

confidence: 52%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

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

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Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1 Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1 Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1 Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1 Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1 Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.T ransducin-like enhancer of split 1 (TLE1) belongs to a family of corepressor proteins called transducin-like enhancer of split, or TLEs. Groucho, the TLE homolog in Drosophila, has crucial roles in neurogenesis, segmentation, and sex determination (1). These corepressors do not bind directly to DNA but rather interact with many different classes of transcription factors and help create a repressor complex (1, 2).Vertebrates express five different TLEs (TLE1-4, AES), although the distinct functions of each of the TLEs has not been well determined. TLE1, the most studied among the Groucho family proteins in mammalian systems, is widely expressed in different tissues and cell types and has been implicated in neuronal differentiation (3, 4) and pancreatic beta cell development (5). TLE1 has tumor suppressor activity (6-8) as well as oncogenic functions in cancer (9, 10). TLE1 associates with many important transcription factors integral for cell proliferation and differentiation, including Runx2 to block rRNA expression (11), HES1 to suppresses MASH2 expression (12), and TCF/LEF proteins to block Wnt target gene activation (13). TLE1 also represses NF-κB activity (14,15). Involvement in these diverse cellular functions and diseases was studied primarily in vitro or using in vivo overexpression systems. The major physiological function of TLE1, however, remains poorly understood.A few recent studies suggest TLE1 might regulate immune function. For example, a single noncoding nucleotide polymorphism within the TLE1 locus was associated with inflammatory bowel diseases (16), and in human monocytes,...

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Section: Discussionsupporting

confidence: 52%

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Ramasamy

Sáez

Mukhopadhyay

et al. 2016

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

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“…Members of the interferon regulatory factor (IRF) family of transcription factors mainly act as regulators of host defense and inflammation [27][28][29][30]. Inflammatory activation of early HSCs has been shown to be evolutionarily conserved [38], and a recent report by Hall et al [31] demonstrated that, in zebrafish, Gcsfr-NO signaling is required for the expansion of HSCs following infection. Among the irf family members, irf8 was shown to be required for myeloid differentiation into macrophages as opposed to neutrophils [39] and for the regulation of B-cell lineage specification and differentiation [40].…”

Section: Discussionmentioning

confidence: 99%

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

et al. 2013

Cell Res

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Previous studies on developmental hematopoiesis have mainly focused on signaling and transcription factors, while the appreciation of epigenetic regulation including that of microRNAs is recent. Here, we show that in zebrafish and mouse, miR-142-3p is specifically expressed in hematopoietic stem cells (HSCs). Knockdown of miR-142a-3p in zebrafish led to a reduced population of HSCs in the aorta-gonad-mesonephros (AGM) region as well as T-cell defects in the thymus. Mechanistically, miR-142a-3p regulates HSC formation and differentiation through the repression of interferon regulatory factor 7 (irf7)-mediated inflammation signaling. Finally, we show that miR-142-3p is also involved in the development of HSCs in mouse AGM, suggesting that it has a highly conserved role in vertebrates. Together, these findings unveil the pivotal roles that miR-142a-3p plays in the formation and differentiation of HSCs by repressing irf7 signaling.

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“…5 Postnatally, hematopoiesis occurs inside soft tissues of BM cavities. During the past decades, a tremendous body of knowledge has been gained regarding the multistep stem cell differentiation process and its regulation by transcription factor pathways.…”

Section: Hematopoiesis: a Paradigm To Study Tissue Stem Cell-based Mamentioning

confidence: 99%

The science behind the hypoxic niche of hematopoietic stem and progenitors

Nombela‐Arrieta

Silberstein

2014

Hematology

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In blood, oxygen is transported principally by hemoglobin tetrameric molecules in erythocytes, which allow for the delivery to tissue cells. When anemia occurs, such as perisurgically or after trauma, blood transfusion is administered to replace the deficit in oxygen-carrying capacity. During embryogenesis and later in adult life, tissue oxygen levels control multiple key cellular functions. Low tissue oxygen levels in particular are physiologically relevant to stem cells by controlling their metabolism and cell fate. In adult life, hematopoietic stem cells reside in specified BM microenvironments/niches, where their quiescence and differentiation are presumably also influenced by cell-intrinsic and cell-extrinsic (niche) factors. Novel imaging technologies have allowed determination of the spatial localization of hematopoietic stem/progenitor cells (HSPCs), as well as the topography of oxygen distribution in BM cavities. Together, these recent advances have contributed to the emergence of a novel model that challenges the previous concept of a hypoxic hematopoietic stem cell niche characterized by poorly perfused endosteal zones with the deepest hypoxia. HSPCs display a hypoxic phenotype despite residing in close association with arterial or sinusoidal vascular networks. The entire BM cavity is hypoxic and unexpectedly exhibits an opposite oxygen gradient to the one initially proposed because arteriole-rich endosteal zones are relatively less hypoxic than deeper regions of the BM perfused by dense sinusoidal networks. Therefore, further studies are warranted to elucidate to what extent differences in oxygen tensions in these diverse microenvironments influence HSPC homeostasis. Learning Objective• To understand the fundamental basic research carried out to investigate the relevance of hypoxic conditions in bone marrow microenvironments that support hematopoietic stem cell maintenance Oxygen in tissues and stem cell biologyDuring evolution, fluctuations in atmospheric oxygen concentration have defined eukaryotic life forms on earth, exemplified by the adoption of efficient oxidative phosphorylation (ie, aerobic metabolism) to support more complex and multicellular organisms. 1

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Demand-adapted regulation of early hematopoiesis in infection and inflammation

Cited by 370 publications

References 126 publications

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates

The science behind the hypoxic niche of hematopoietic stem and progenitors

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