Effect of Transcription Factor GATA-2 on Phagocytic Activity of Alveolar Macrophages from<i>Pneumocystis carinii</i>-Infected Hosts

Lasbury, Mark E.; Tang, Xing; Durant, Pamela J.; Lee, Chao‐Hung

doi:10.1128/iai.71.9.4943-4952.2003

Cited by 50 publications

(52 citation statements)

References 43 publications

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“…Furthermore, once GATA2 is overexpressed in infected macrophages, they reacquire phagocytic activity. 28 Therefore, our results corroborate the observation that preadipocytes behave like macrophages. 3 However, we observed that preadipocytes expressing GATA2 do not bear a typical macrophage marker like F4/80, indicating that they are not fully converted into macrophages.…”

Section: Discussionsupporting

confidence: 82%

Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue–Related Inflammation

et al. 2005

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Background-Obesity-related inflammation is emerging as a major cause of insulin resistance and cardiovascular diseases.GATA2 transcription factor is an inhibitor of adipogenesis and an activator of vascular cells. We hypothesized that GATA2 activity is controlled by insulin during adipogenesis, linking metabolic homeostasis and inflammation. Methods and Results-We show that insulin induces GATA2 phosphorylation on serine 401 in a PI-3K/Akt-dependent manner.Insulin-dependent phosphorylation of serine 401 impairs GATA2 translocation to the nucleus and its DNA binding activity. A GATA2 mutant not phosphorylable by Akt (GATA2 S401A ) acts similarly to wild-type GATA2. In contrast, a GATA2 mutant that mimics Akt phosphorylation (GATA2 S401D ) is restrained in the cytoplasm. Cultured preadipocytes bearing GATA2 S401A do not convert to adipocytes and express high levels of inflammatory cytokines like monocyte chemotactic protein-1 (MCP-1). On the contrary, GATA2 S401D preadipocytes differentiate to adipocytes. When GATA2 S401A preadipocytes are injected in mice fed a high-fat diet, they do not differentiate adequately into adipocytes, maintaining the expression of inflammatory markers like MCP-1. In contrast, injection of GATA2 S401D preadipocytes in mice fed a high-fat diet results in development of adipocytes and no expression of inflammatory markers. Conclusions-GATA2 could be a new target in the prevention and treatment of obesity-related inflammation and its complications.

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Section: Discussionsupporting

confidence: 82%

Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue–Related Inflammation

et al. 2005

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“…Macrophage mannose receptor expression is also down-regulated (10), although the shed form of the mannose receptor is increased (11), which may help the organism evade host immune responses (7,10,11). The expression of the transcription factor GATA-2 is reduced in alveolar macrophages during Pcp 2 (12), and this GATA-2 down-regulation is correlated with the dysfunction of alveolar macrophages (13). There is a decrease in plasma S-adenosylmethionine levels during the infection (14).…”

mentioning

confidence: 99%

Polyamine-mediated Apoptosis of Alveolar Macrophages during Pneumocystis Pneumonia

Lasbury

Merali

Durant

et al. 2007

Journal of Biological Chemistry

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The number of alveolar macrophages is decreased during Pneumocystis pneumonia (Pcp), partly because of activation of apoptosis in these cells. This apoptosis occurs in both rat and mouse models of Pcp. Bronchoalveolar lavage (BAL) fluids from Pneumocystis-infected animals were found to contain high levels of polyamines, including spermidine, N 1 -acetylspermine, and N 1 -acetylspermidine. These BAL fluids and exogenous polyamines were able to induce apoptosis in alveolar macrophages. Apoptosis of alveolar macrophages during infection, after incubation with BAL fluids from Pneumocystis-infected animals, or after incubation with polyamines was marked by an increase in intracellular reactive oxygen species, activation of caspases-3 and -9, DNA fragmentation, and leakage of mitochondrial cytochrome c into the cytoplasm. When polyamines were depleted from the BAL fluids of infected animals, the ability of these BAL fluids to induce apoptosis was lost. Interestingly, the apoptosis inducing activity of the polyamine-depleted BAL fluids was restored when polyamines were added back. The results of this study suggested that Pneumocystis infection results in accumulation of high levels of polyamines in the lung. These polyamines activate apoptosis of alveolar macrophages, perhaps because of the ROS that are produced during polyamine metabolism.Pneumocystis-infected lungs usually contain much alveolar exudate and numerous inflammatory cells in perivascular and peribronchiolar areas (1-3). The infection also causes changes in the lung. One such change is significantly increased levels of surfactant proteins A and D (4, 5). These collectins are implicated in the attachment of Pneumocystis to alveolar epithelial cells during infection (4 -6) and evasion of the host immune response (7). In contrast, surfactant proteins B (8) and C (4, 9) are down-regulated in their expression. Macrophage mannose receptor expression is also down-regulated (10), although the shed form of the mannose receptor is increased (11), which may help the organism evade host immune responses (7,10,11). The expression of the transcription factor GATA-2 is reduced in alveolar macrophages during Pcp 2 (12), and this GATA-2 down-regulation is correlated with the dysfunction of alveolar macrophages (13). There is a decrease in plasma S-adenosylmethionine levels during the infection (14). The infection also causes erosion of type I pneumocytes and proliferation of type II epithelial cells (15). These changes indicate that Pneumocystis mediates many alterations in pulmonary and systemic environments in an effort to survive in the host.In addition to these changes, the number of alveolar macrophages is decreased during Pcp in humans (16 -20) and in a rat model of infection (21). This change may be due to decreased precursor cell recruitment or maturation, increased efflux of cells from the lung, increased apoptosis rate, or a combination of these factors. Apoptosis is a normal event in development or tissue turnover (22) and can also be a response to disease stat...

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“…However, the overall ever-smoking rate (including former smokers) is approximately 29% in our adult GATA2 cohort. We hypothesize that the known effect of smoking on alveolar macrophages may be markedly accentuated in patients with primary monocyte/macrophage dysfunction, such as GATA2 deficiency, increasing the risk of disseminated disease (12). Disseminated M. kansasii disease is a rare complication seen in a limited number of immunodeficiency conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of GATA2 contributes susceptibility to severe and disseminated viral (e.g., human papillomavirus), fungal, and NTM infections, pulmonary alveolar proteinosis, and myelodysplastic syndrome (MDS) (11). The hematologic profile of patients includes deficiencies of NK cells, monocytes, and B cells, and down-regulation of GATA2 has also been associated with impaired phagocytic activity of alveolar macrophages (12).…”

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confidence: 99%

Mediastinal and Disseminated Mycobacterium kansasii Disease in GATA2 Deficiency

et al. 2016

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Rationale: Mycobacterium kansasii usually causes chronic pulmonary infections in immunocompetent patients. In contrast, disseminated M. kansasii disease is commonly associated with advanced human immunodeficiency virus infection, but is reported infrequently in other immunocompromised patients.Objectives: To identify common clinical manifestations and potential risk factors for M. kansasii infection in patients with GATA2 deficiency.Methods: We reviewed M. kansasii disease associated with GATA2 deficiency at one institution and disease associated with primary and other immunodeficiencies reported in the literature. Measurements and Main Results:Nine patients with GATA2 deficiency developed M. kansasii infections. Six patients developed disseminated disease. All patients presented with significant mediastinal lymphadenopathy or abscesses. Seven patients had pulmonary risk factors, including six smokers. The majority of patients had low numbers of neutrophils, monocytes, B cells, CD4 1 T cells, and natural killer cells. Other conditions associated with disseminated M. kansasii disease were thymic disorders and IFN-g/IL-12 defects.Conclusions: Disseminated M. kansasii disease involving mediastinal lymph nodes is surprisingly common in GATA2 deficiency, but also occurs in defects of IFN-g synthesis and response. Disseminated M. kansasii should be considered a marker indicating a need to evaluate for immunodeficiency syndromes.

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Effect of Transcription Factor GATA-2 on Phagocytic Activity of Alveolar Macrophages fromPneumocystis carinii-Infected Hosts

Cited by 50 publications

References 43 publications

Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue–Related Inflammation

Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue–Related Inflammation

Polyamine-mediated Apoptosis of Alveolar Macrophages during Pneumocystis Pneumonia

Mediastinal and Disseminated Mycobacterium kansasii Disease in GATA2 Deficiency

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