Osteoclasts are derived from mononuclear phagocyte lineage cells and are indispensable for bone resorption. Recent findings suggest that fetal yolk sac macrophage progenitors give rise to neonatal ...osteoclasts, while hematopoietic stem cell-derived cells, such as monocytes, contribute to maintaining osteoclast syncytia in vivo. Osteoclast differentiation is dependent on macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) signaling that mediates global epigenetic and transcriptional changes. PU.1 is a transcription factor that establishes cell type-specific enhancer landscapes in osteoclast precursors and mature osteoclasts by collaborating with interferon regulatory factor-8 (IRF8) and nuclear factor of activated T-cells (NFATc1), respectively. Irf8 and Nfatc1 genes are tightly controlled by epigenetic mechanisms such as DNA methylation and histone modifications during osteoclastogenesis. Thus, key transcription factors orchestrate osteoclast-specific transcription regulatory networks through epigenetic modifications. In this review, we discuss recent advances in our understanding of the molecular mechanisms involved in osteoclast development.
•PU.1 establishes enhancer landscapes in osteoclast precursors and mature osteoclasts.•RANKL signaling stimulates an osteoclast-specific transcriptional program.•PU.1 switches its binding partner from IRF8 to NFATc1 during osteoclastogenesis.
The interferon regulatory factor (IRF) family, consisting of nine members in mammals, was identified in the late 1980s in the context of research into the type I interferon system. Subsequent studies ...over the past two decades have revealed the versatile and critical functions performed by this transcription factor family. Indeed, many IRF members play central roles in the cellular differentiation of hematopoietic cells and in the regulation of gene expression in response to pathogen-derived danger signals. In particular, the advances made in understanding the immunobiology of Toll-like and other pattern-recognition receptors have recently generated new momentum for the study of IRFs. Moreover, the role of several IRF family members in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.
We investigated the taxonomic relationships among
Streptomyces diastaticus
subsp.
ardesiacus
,
Streptomyces diastaticus
subsp.
diastaticus
,
Streptomyces gougerotii
and
Streptomyces rutgersensis
. ...The 16S rRNA gene sequence similarity between
S. diastaticus
subsp.
ardesiacus
and
S. diastaticus
subsp.
diastaticus
was 97.7 %, whereas
S. diastaticus
subsp.
diastaticus
,
S. gougerotii
and
S. rutgersensis
showed 100 % nucleotide sequence identity. In addition,
S. diastaticus
subsp. diastaticus
, S. gougerotii
and
S. rutgersensis
formed a single clade in the phylogenetic tree. Digital DNA–DNA relatedness between
S. diastaticus
subsp.
diastaticus
and
S. diastaticus
subsp.
ardesiacus
was only 22.8%, indicative of different species. In comparison, DNA–DNA relatedness values for
S. diastaticus
subsp.
diastaticus
,
S. gougerotii
and
S. rutgersensis
ranged from 95.8 to 97.2 %, suggesting the three taxa belong to the same genomospecies. Previously reported phenotypic data also supported synonymy. Therefore, we propose that
S. diastaticus
subsp.
ardesiacus
should be classified as an independent species,
Streptomyces ardesiacus
sp. nov. The type strain is NBRC 13412
T
(=ATCC 3315
T
=CBS 713.72
T
=DSM 40496
T
=ISP 5496
T
=JCM 4745
T
=NBRC 3714
T
=NRRL B-1241
T
=RIA 1373
T
). Our data also suggests that
S. rutgersensis
and
S. gougerotii
should be reclassified as later heterotypic synonyms of
S. diastaticus
.
Monocytes and macrophages play critical roles in immune responses, tissue homeostasis and disease progression. There are a number of functionally and phenotypically distinct subpopulations throughout ...the body. However, the mechanisms by which macrophage and monocyte heterogeneity is established remain unclear. Recent studies have suggested that most tissue-resident macrophages originate from fetal progenitors but not from hematopoietic stem cells, whereas some subpopulations are derived from adult monocytes. In addition, transcription factors specifically required for the development of each subpopulation have been identified. Interestingly, local environmental factors such as heme, retinoic acid and RANKL induce the expression and/or activation of tissue-specific transcription factors, thereby controlling transcriptional programs specific for the subpopulations. Thus, distinct differentiation pathways and local microenvironments appear to contribute to the determination of macrophage transcriptional identities. In this review, we highlight recent advances in our knowledge of the transcriptional control of macrophage and monocyte development.
Abstract
The transcription factor interferon regulatory factor-5 (IRF5) plays an important role in innate immune responses via the TLR-MyD88 (Toll-like receptor - myeloid differentiation primary ...response 88) pathway. IRF5 is also involved in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Recent studies have identified new regulators, both positive and negative, which act on IRF5 activation events in the TLR-MyD88 pathway such as post-translational modifications, dimerization and nuclear translocation. A model of the causal relationship between IRF5 activation and SLE pathogenesis proposes that a loss of the negative regulation of IRF5 causes its hyperactivation, resulting in hyperproduction of type I interferons and other cytokines, and ultimately in the development of SLE. Importantly, to our knowledge, all murine models of SLE studied thus far have shown that IRF5 is required for the pathogenesis of SLE-like diseases. During the development of SLE-like diseases, IRF5 plays key roles in various cell types, including dendritic cells and B cells. It is noteworthy that the onset of SLE-like diseases can be inhibited by reducing the activity or amount of IRF5 by half. Therefore, IRF5 is an important therapeutic target of SLE, and selective suppression of its activity and expression may potentially lead to the development of new therapies.
Abstract
The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease ...course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional
Irf5
deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.
ABSTRACT
Macrophages are extremely heterogeneous mononuclear phagocytes widely distributed throughout the body. They play unique roles in each organ where they reside. Among macrophage subsets, red ...pulp macrophages (RPMs) that localize in the splenic red pulp, are critical for maintenance of blood homeostasis by actively phagocytosing injured and senescent erythrocytes and blood‐borne particulates. Recent evidence indicates that RPMs are mainly generated during embryogenesis and are maintained during adult life. Furthermore, the cell‐intrinsic and ‐extrinsic factors (namely, Spi‐C, IRF8/4, heme oxygenase‐1, and M‐CSF) that regulate the development and survival of RPMs have been identified. Although the immunological properties of RPMs have yet to be elucidated fully, pioneering studies have demonstrated that these cells are capable of inducing differentiation of regulatory T cells via expression of transforming growth factor‐β and secrete a large amount of type I interferons during parasitic infections. In this review, we describe recent advances in understanding of the functions and development of RPMs.
Nine interferon regulatory factors (IRFs) compose a family of transcription factors in mammals. Although this family was originally identified in the context of the type I interferon system, ...subsequent studies have revealed much broader functions performed by IRF members in host defense. In this review, we provide an update on the current knowledge of their roles in immune responses, immune cell development, and regulation of oncogenesis.
A family of transcription factors, the interferon regulatory factors (IRF), was identified originally in the context of the regulation of the type I interferon (IFN)‐α/β system. The IRF family has ...now expanded to nine members, and gene‐disruption studies have revealed the critical involvement of these members in multiple facets of host defense systems, such as innate and adaptive immune responses and tumor suppression. In the present review article, we aim at summarizing our current knowledge of the roles of IRF in host defense, with special emphasis on their involvement in the regulation of oncogenesis. (Cancer Sci 2008; 99: 467–478)