ATF3 is a novel regulator of mouse neutrophil migration

Boespflug, Nicholas D.; Kumar, Sachin; McAlees, Jaclyn W.; Phelan, James D.; Grimes, H. Leighton; Hoebe, Kasper; Hai, Tsonwin; Filippi, Marie–Dominique; Karp, Christopher L.

doi:10.1182/blood-2013-06-510909

Cited by 62 publications

(63 citation statements)

References 42 publications

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“…ATF3 was shown to be important for neutrophil migration in the lungs via transrepression of CXCL1 chemokine (38). Another study reported that ATF3 functions as a novel negative regulator of neutrophil differentiation by modulating Ly6G expression (39).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Liu

Wei

Shi

et al. 2016

Journal of Biological Chemistry

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Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Liu

Wei

Shi

et al. 2016

Journal of Biological Chemistry

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“…As CXCR2 ligands were particularly downregulated in airway epithelium, we investigated whether recombinant CXCL1, CXCL2, or CXCL5 could rescue impaired bacterial clearance in the ethanol group. Local delivery of recombinant CXCL1 and CXCL5 (doses used in previous studies [16][17][18]) but not CXCL2 significantly decreased bacterial burden compared to the ethanol group that received vehicle control (Fig. 6C).…”

Section: (Paired T Test) (B) Gene Expression Data From Panelmentioning

confidence: 98%

Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression

et al. 2015

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Acute ethanol intoxication suppresses the host immune responses against Streptococcus pneumoniae. As interleukin 17 (IL-17) is a critical cytokine in host defense against extracellular pathogens, including S. pneumoniae, we hypothesized that ethanol impairs mucosal immunity against this pathogen by disrupting IL-17 production or IL-17 receptor (IL-17R) signaling. A chronic ethanol feeding model in simian immunodeficiency virus (SIV)-infected rhesus macaques and acute ethanol intoxication in a murine model were used. Transcriptome analysis of bronchial brushes in the nonhuman primate model showed downregulation of the expression of IL-17-regulated chemokines in ethanol-fed animals, a finding also replicated in the murine model. Surprisingly, recombinant CXCL1 and CXCL5 but not IL-17 or IL-23 plus IL-1␤ rescued bacterial burden in the ethanol group to control levels. Taken together, the results of this study suggest that ethanol impairs IL-17-mediated chemokine production in the lung. Thus, exogenous luminal restoration of IL-17-related chemokines, CXCL1 and CXCL5, improves host defenses against S. pneumoniae. Bacterial pneumonia is a complication of ethanol abuse, and this susceptibility was documented both in animal models and in human studies more than a century ago (1, 2). Excessive ethanol consumption remains a public health problem responsible for approximately 79,000 deaths in the United States each year and for an estimated economic cost of $223.5 billion in 2006 (3).Streptococcus pneumoniae is a Gram-positive bacterium and the leading etiology of community-acquired pneumonia, especially in older adults and alcoholic patients. Innate immune responses are important to control infections by S. pneumoniae, as evidenced by the roles of Toll-like receptors, MyD88, and IRAK4 in both humans and animal models (4, 5). More recently, evidence has emerged to support the fact that interleukin 17 (IL-17) plays a critical role in the regulation of S. pneumoniae colonization and infection. IL-17 and CD4 ϩ T cells, and specifically the Th17 subset, are important for clearance of nasopharyngeal colonization with S. pneumoniae (a prerequisite of pneumococcal pneumonia) during primary and secondary infection (6, 7).IL-17 is a cytokine produced by activated CD4 ϩ T cells and innate lymphocytes (␥␦ ϩ T cells, NK cells, and innate lymphoid cells) and drives inflammation and autoimmunity (8). In the lung, the airway epithelium plays an important role in orchestrating the production of C-X-C chemokines, and these cells express both IL-17RA and IL-17RC and can produce both C-X-C chemokines and granulocyte colony-stimulating factor (G-CSF) in response to IL-17, leading to neutrophil recruitment in vivo (9-11).As the lung epithelium is a major site of chemokine production during bacterial pneumonia (12), we examined the effect of ethanol on gene expression in the airway epithelium during experimental S. pneumoniae infection in a nonhuman primate model of ethanol consumption and pneumococcal infection (13,14). We analyzed bronchial b...

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“…27 In neutrophils, ATF3 reduced expression of chemokines, such as C-X-C motif ligand 1 (CXCL1), but promoted neutrophil chemotaxis. 28 In primary human monocytes and macrophages, IFN-γ significantly induced ATF3 expression, which in turn bound to the promoter of matrix metalloproteinase 1 (MMP-1), reducing its transcription. 29 IFN-β induced ATF3 expression, which binds to a distal regulatory sequence of IFN-β to reduce its transcription.…”

Section: Role Of Atf3 In Immune Functionmentioning

confidence: 99%

Activating transcription factor 3 in immune response and metabolic regulation

Jadhav

Zhang

2017

Liver Research

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Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element binding protein (CREB) family of transcription factors. In response to stress stimuli, ATF3 forms dimers to activate or repress gene expression. Further, ATF3 modulates the immune response, atherogenesis, cell cycle, apoptosis, and glucose homeostasis. Recent studies have shown that ATF3 may also be involved in pathogenesis of other diseases. However, more studies are needed to determine the role of ATF3 in metabolic regulation.

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ATF3 is a novel regulator of mouse neutrophil migration

Abstract: Key Points ATF3 inhibits lipopolysaccharide-driven CXCL1 production by airway epithelia. ATF3 controls neutrophil recruitment to the wild-type lung and chemotaxis in vitro via TIAM2 expression.

Cited by 62 publications

References 42 publications

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression

Activating transcription factor 3 in immune response and metabolic regulation

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