Pneumocystis Mediates Overexpression of Antizyme Inhibitor Resulting in Increased Polyamine Levels and Apoptosis in Alveolar Macrophages

Liao, Chung Ping; Lasbury, Mark E.; Wang, Shao Hung; Zhang, Chen; Durant, Pamela J.; Murakami, Yasuko; Matsufuji, Senya; Lee, Chao Hung

doi:10.1074/jbc.m805787200

Cited by 22 publications

(19 citation statements)

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“…Viability of the organisms was also not a factor in altering calmodulin mRNA levels; therefore, the molecule(s) responsible for downregulating the expression of calmodulin may be a soluble factor(s) from the host or organism. Previous reports have implicated ␤-glucan (15, 37), the major surface glycoprotein (6,34), and polyamines from the organism (35,37) in modulation of host cell functions.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of Amø renders animals susceptible to Pneumocystis pneumonia (Pcp) (47), while increased Amø numbers retard progression of the disease (33; M. E. Lasbury submitted for publication). Low Amø numbers in animals with Pcp are caused by increased apoptosis, which is related to the catabolism of intracellular polyamines and production of hydrogen peroxide (35,37). Reduced survival pathway signaling and antioxidant expression also contribute to the apoptosis of Amø during Pcp (Lasbury, submitted).…”

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Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

et al. 2009

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Pneumocystis infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during Pneumocystis pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.

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Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

et al. 2009

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“…In a surprising revelation, recent studies have identified significant AM apoptosis during P. murina infection (13) that appears to be mediated by immune cell polyamine and peroxide production (14). Mechanistic studies demonstrated that the observed AM apoptosis was a result of Pneumocystis organisms inducing antizyme inhibitor overexpression in AMs, leading to increased polyamine synthesis and uptake (15).…”

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IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Nelson

Christmann²,

Metz

et al. 2011

B14. Novel Treatments for Lung Infections: Modulating Immune Responses

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We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis. Pneumonia caused by NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwere diagnosed in the year 2009, and 25,000 deaths (19,000 in 2002) were recorded as a result of HIV infection (2). Although the advent of highly active antiretroviral therapy (HAART) has decreased the overall incidence of Pneumocystis carinii pneumonia (3), the mortality rate of those requiring hospitalization remains high (3). A recent retrospective study in an academic medical center found that overall hospital mortality rate to P. jiroveci pneumonia was 11.6%, and in those patients requiring intensive care, 29.0% (4). An additional study summarized the experience with HIV-associated P. carinii pneumonia over a 21-y period in a single center and found that mortality was 10.1% for the period from 1985 through 1989, 16.9% for the period from 1990 through June 1996, and 9.7% for the period from July 1996 through 2006 (i.e., the HAART era) (5). A major concern voiced by this study is the similar mortality associated with P. jiroveci pneumonia pre-and post-HAART.It is widely reported that phagocytosis by alveolar macrophages (AMs) is the predominant mechanism of Pneumocystis murina clearance from the lungs (6-8); however, the mechanisms by which macrophages kill P. murina are not completely understood. It is hypothesized that on phagocytosis, the oxidative burst b...

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“…Although alveolar macrophages (AMs) play an important role in the clearance of microorganisms in the lungs, they are defective in phagocytosis (1,2), and their number is decreased during PcP (3)(4)(5)(6)(7)(8). A cause of this AM number decrease is increased apoptosis due to elevated levels of intracellular polyamines (9,10). The causes for AM dysfunction during PcP are not clear; one possible cause is downregulation of the transcription factor PU.1 (11), as it regulates the expression of many macrophage receptors (11)(12)(13)(14)(15).…”

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Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

2015

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Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1 ؉ cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.

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Pneumocystis Mediates Overexpression of Antizyme Inhibitor Resulting in Increased Polyamine Levels and Apoptosis in Alveolar Macrophages

Cited by 22 publications

References 51 publications

Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

Effects of Decreased Calmodulin Protein on the Survival Mechanisms of Alveolar Macrophages during Pneumocystis Pneumonia

IL-33 And M2A Alveolar Macrophages Promote Lung Defense Against The Atypical Fungal Pathogen Pneumocystis Murina

Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

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