Suppression of Alveolar Macrophage Apoptosis Prolongs Survival of Rats and Mice with<i>Pneumocystis</i>Pneumonia

Lasbury, Mark E.; Durant, Pamela J.; Ray, Chad; Tschang, Dennis; Schwendener, Reto A.; Lee, Chao‐Hung

doi:10.4049/jimmunol.176.11.6443

Cited by 43 publications

(48 citation statements)

References 57 publications

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“…Furthermore, their marked suppressive activities may in some situations exert beneficial effects during exuberant host inflammation, including activity in suppressing TNF-a and macrophage inflammatory protein-2 (36,37). Inflammatory responses by macrophages and epithelial cells also provide important functions in Pneumocystis host defense (67,68). However, caution must be exercised, because these agents may also suppress important DC/lymphocyte-based IL-23/IL-17 responses, which are required to clear fungal infections.…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Carmona

Kottom

Hebrink

et al. 2012

Am J Respir Cell Mol Biol

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Pneumocystis species are opportunistic fungal organisms that cause severe pneumonia in immune-compromised hosts, with resultant high morbidity and mortality. Recent work indicates that IL-17 responses are important components of host defense against fungal pathogens. In the present study, we demonstrate that cellsurface b-glucan components of Pneumocystis (PCBG) stimulate human dendritic cells (DCs) to secrete IL-23 and IL-6. These cytokines are well established to stimulate a T helper-17 (Th17) phenotype. Accordingly, we further observe that PCBG-stimulated human DCs interact with lymphocytes to drive the secretion of IL-17 and IL-22, both Th17-produced cytokines. The activation of DCs was shown to involve the dectin-1 receptor with a downstream activation of the Syk kinase and subsequent translocation of both the canonical and noncanonical components of the NF-kB transcription factor family. Finally, we demonstrate that glycosphingolipid-rich microdomains of the plasma membrane participate in the activation of DCs by PCBG through the accumulation of lactosylceramide at the cell surface during stimulation with PCBG. These data strongly support the idea that the b-glucan surface components of Pneumocystis drive the activation of the IL-23/IL-17 axis during this infection, through a glycosphingolipid-initiated mechanism.Keywords: Pneumocystis; b-glucan; dendritic cells; Pneumocystis infection remains an all too common cause of pneumonia in immune-compromised hosts. Before the early 1990s, this infection was largely related to cases of childhood leukemia and infants with severe malnourishment. However, with the onset of the HIV pandemic, Pneumocystis pneumonia (PcP) has emerged as one of most serious causes of pneumonia among this patient population (1-3). In more recent years, an increasing number of PcP cases have been attributed to immunosuppressed individuals with malignancy, or as a result of immunosuppressive agents administered for organ transplantation or autoimmune diseases (4-10).Earlier studies established the central importance of T cells in the host defense against Pneumocystis infection, where CD4 cell counts of less than 200 cells/mm 3 were shown to place individuals at increased risk for this infection (11). More recently, CD4-independent mechanisms were also demonstrated to be important in clearing this infection (12). This is also supported by the fact that patients receiving B cell-suppressive therapy, and animal models of B-cell deficiency, also reveal a higher risk for developing PcP (13,14). Thus, inadequate immune response across multiple components of host defense can render an individual susceptible to this infection.In addition, exaggerated innate inflammatory responses in patients with PcP appear to be associated with a higher risk of developing respiratory failure, as indicated by early work from our laboratory showing that the degree of respiratory failure in immunosuppressed patients with PcP correlated best with the degree of inflammation, and not with the organism burden itself (15...

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Section: Discussionmentioning

confidence: 99%

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Carmona

Kottom

Hebrink

et al. 2012

Am J Respir Cell Mol Biol

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“…Alveolar macrophages that undergo apoptosis in response to S. pneumoniae infection may contribute to enhanced bacterial killing, and additionally restrict the proinflammatory response to inhaled bacteria, thus attenuating overwhelming local and systemic proinflammatory responses to S. pneumoniae infection. At the same time, alveolar and exudate macrophages play important roles in the resolution/repair phase of the disease, thus serving to regain alveolar and lung homeostasis (22)(23)(24)(25)(26). The currently presented data, making use of a largely (yet not exclusively) DC-specific growth factor for the first time, aim at gaining further insights into the role of mononuclear phagocyte subsets other than classical alveolar macrophages in the lung host defense to S. pneumoniae infection and highlight the critical importance of a fine-tuned mononuclear phagocyte network within the lung for an optimal host defense to inhaled bacterial pathogens.…”

Section: Discussionmentioning

confidence: 99%

FMS-Like Tyrosine Kinase 3 Ligand Aggravates the Lung Inflammatory Response to Streptococcus pneumoniae Infection in Mice: Role of Dendritic Cells

Winter¹,

Taut²,

Mack

et al. 2007

The Journal of Immunology

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Pretreatment of mice with the hemopoietic growth factor, FMS-like tyrosine kinase 3 ligand (Flt3L), has been shown to increase monocyte-derived myeloid dendritic cells (DC) in lung parenchymal tissue, with possible implications for protective immunity to lung bacterial infections. However, whether Flt3L treatment improves lung innate immunity of mice to challenge with Streptococcus pneumoniae has not been investigated previously. Mice pretreated with Flt3L exhibited a peripheral monocytosis and a strongly expanded lung myeloid DC pool, but responded with a similar proinflammatory cytokine release (TNF-α, IL-6, keratinocyte derived cytokine, MIP-2, CCL2) and neutrophilic alveolitis upon infection with S. pneumoniae as did control mice with a normal lung DC pool. Unexpectedly, however, Flt3L-pretreated mice, but not control mice, infected with S. pneumoniae developed vasculitis and increased lung permeability by days 2–3 postinfection, and florid pneumonia accompanied by sustained increased bacterial loads by days 3–4 postinfection. This was associated with an overall increased mortality of ∼35% by day 4 after pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block inflammatory monocyte-dependent lung mononuclear phagocyte mobilization significantly reduced the lung leakage, but not vasculitis in Flt3L-pretreated mice infected with S. pneumoniae, without affecting the intra-alveolar cytokine liberation or the concomitantly developing neutrophilic alveolitis. Together, the data demonstrate that previous Flt3L-induced lung DC accumulation is not protective in lung innate immunity to challenge with S. pneumoniae, and support the concept that CCR2-dependent mononuclear phagocyte as opposed to neutrophil recruitment contributes to increased lung leakage in Flt3L-pretreated mice challenged with S. pneumoniae.

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“…Our results indicated that apoptosis contributed to ϳ60% loss of alveolar macrophages during Pcp. This 60% loss of alveolar macrophages by apoptosis is physiologically significant because suppression of this apoptosis by administration of the caspase-9 inhibitor results in decreased organism burdens and increased survival of infected animals (52).…”

Section: Bal Fluids Spermidine Acetylspermine Acetylspermidinementioning

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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Suppression of Alveolar Macrophage Apoptosis Prolongs Survival of Rats and Mice withPneumocystisPneumonia

Cited by 43 publications

References 57 publications

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

FMS-Like Tyrosine Kinase 3 Ligand Aggravates the Lung Inflammatory Response to Streptococcus pneumoniae Infection in Mice: Role of Dendritic Cells

Polyamine-mediated Apoptosis of Alveolar Macrophages during Pneumocystis Pneumonia

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