Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus

ABSTRACTExposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.

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S100A4 Regulates Macrophage Chemotaxis

Molecular Biology of the Cell ◽

10.1091/mbc.e09-07-0609 ◽

2010 ◽

Vol 21 (15) ◽

pp. 2598-2610 ◽

Cited By ~ 79

Author(s):

Zhong-Hua Li ◽

Natalya G. Dulyaninova ◽

Reniqua P. House ◽

Steven C. Almo ◽

Anne R. Bresnick

Keyword(s):

Tumor Metastasis ◽

Colony Stimulating Factor ◽

S100 Family ◽

Macrophage Chemotaxis ◽

Primary Bone ◽

Stimulating Factor ◽

Deficient Mice ◽

Primary Bone Marrow

S100A4, a member of the S100 family of Ca2+-binding proteins, is directly involved in tumor metastasis. In addition to its expression in tumor cells, S100A4 is expressed in normal cells and tissues, including fibroblasts and cells of the immune system. To examine the contribution of S100A4 to normal physiology, we established S100A4-deficient mice by gene targeting. Homozygous S100A4−/−mice are fertile, grow normally and exhibit no overt abnormalities; however, the loss of S100A4 results in impaired recruitment of macrophages to sites of inflammation in vivo. Consistent with these observations, primary bone marrow macrophages (BMMs) derived from S100A4−/−mice display defects in chemotactic motility in vitro. S100A4−/−BMMs form unstable protrusions, overassemble myosin-IIA, and exhibit altered colony-stimulating factor-1 receptor signaling. These studies establish S100A4 as a regulator of physiological macrophage motility and demonstrate that S100A4 mediates macrophage recruitment and chemotaxis in vivo.

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Macrophage colony-stimulating factor-induced bone marrow macrophages do not synthesize or release prostaglandin E2

Blood ◽

10.1182/blood.v83.11.3316.3316 ◽

1994 ◽

Vol 83 (11) ◽

pp. 3316-3323 ◽

Cited By ~ 8

Author(s):

Y Shibata ◽

DR Bjorkman ◽

M Schmidt ◽

Y Oghiso ◽

A Volkman

Keyword(s):

Bone Marrow ◽

Enzyme Activity ◽

Prostaglandin E2 ◽

Bone Marrow Cells ◽

Mrna Levels ◽

Colony Stimulating Factor ◽

Murine Bone Marrow ◽

Gm Csf ◽

Stimulating Factor

Abstract Previously, we found that murine bone marrow-derived macrophages (MO) induced in vitro by MO-specific colony-stimulating factor (M-CSF) have little capacity to release prostaglandin E2 (PGE2) and other eicosanoids. This work focused on the functional and transcriptional expression of the key enzymes for the PGE2 synthesis in the MO. Nonadherent bone marrow cells were cultured with RPMI1640 plus 10% fetal bovine serum (FBS) further supplemented with either M-CSF or granulocyte-macrophage (GM)-CSF and interleukin-3 (IL-3). Cellular PGG/H synthase (cyclooxygenase) levels were quantified by cytometric analysis with antibodies specific for the two isozymes of PGG/H synthase (PGG/H synthases 1 and 2). The enzyme activity was monitored by adding exogenous arachidonic acid (AA) substrate to the bone marrow MO cultures and to the cell-free particulate fractions. The levels of PGE2 converted were quantitated by radioimmunoassay (RIA). mRNA levels of the enzymes were detected by Northern blot analysis hybridized with mouse PGG/H synthase cDNA probes, 2.7 kb (PGG/H synthase 1) and 4.2 kb (PGG/H synthase 2). In addition, cellular phospholipase A2 (PLA2) activities were detected with sn-2–14C-arachidonyl phosphatidylcholine as a substrate. Cells proliferating in the presence of GM-CSF and IL-3 for more than 4 days showed significant release of PGE2 (> 7 ng/10(6) cells) when stimulated by AA. These cells also expressed significant amounts of PGG/H synthase 1 protein, its mRNA (2.7 kb) and cellular PLA2. M-CSF-induced MO, in sharp contrast, expressed little PGG/H synthase protein, mRNA, cellular enzyme activity, or PGE2 release, despite comparable levels of cellular PLA2 activity. These data suggest that the capacity of differentiating marrow-derived MO to form PGE2 is growth factor-dependent.

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Vitamin D Regulation of OX40 Ligand in Immune Responses to Aspergillus fumigatus

Infection and Immunity ◽

10.1128/iai.01345-12 ◽

2013 ◽

Vol 81 (5) ◽

pp. 1510-1519 ◽

Cited By ~ 18

Author(s):

Nikki Lynn Hue Nguyen ◽

Kong Chen ◽

Jeremy Mcaleer ◽

Jay K. Kolls

Keyword(s):

Vitamin D ◽

Aspergillus Fumigatus ◽

Vitamin D Deficiency ◽

Costimulatory Molecule ◽

Allergic Bronchopulmonary Aspergillosis ◽

Content Type ◽

Ox40 Ligand ◽

Th2 Responses

ABSTRACTOX40 ligand (OX40L) is a costimulatory molecule involved in Th2 allergic responses. It has been shown that vitamin D deficiency is associated with increased OX40L expression in peripheral CD11c+cells and controls Th2 responses toAspergillus fumigatusin vitroin cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA). To investigate if vitamin D deficiency regulated OX40L and Th2 responsesin vivo, we examined the effect of nutritional vitamin D deficiency on costimulatory molecules in CD11c+cells andA. fumigatus-induced Th2 responses. Vitamin D-deficient mice showed increased expression of OX40L on lung CD11c+cells, and OX40L was critical for enhanced Th2 responses toA. fumigatusin vivo. Inin vitroassays, vitamin D treatment led to vitamin D receptor (VDR) binding in the promoter region of OX40L and significantly decreased the promoter activity of the OX40L promoter. In addition, vitamin D altered NF-κB p50 binding in the OX40L promoter that may be responsible for repression of OX40L expression. These data show that vitamin D can act directly on OX40L, which impacts Th2 responses and supports the therapeutic use of vitamin D in diseases regulated by OX40L.

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Differential Modulation of Listeria monocytogenes Fitness, In Vitro Virulence, and Transcription of Virulence-Associated Genes in Response to the Presence of Different Microorganisms

Applied and Environmental Microbiology ◽

10.1128/aem.01165-20 ◽

2020 ◽

Vol 86 (17) ◽

Author(s):

Evangelia A. Zilelidou ◽

Varvara Milina ◽

Spiros Paramithiotis ◽

Georgia Zoumpopoulou ◽

Sofia V. Poimenidou ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Virulence Genes ◽

Biological Activities ◽

Survival Strategies ◽

Cell Contact ◽

Mrna Levels ◽

Limited Information ◽

Content Type ◽

The Impact

ABSTRACT Interactions between Listeria monocytogenes and food-associated or environmental bacteria are critical not only for the growth but also for a number of key biological processes of the microorganism. In this regard, limited information exists on the impact of other microorganisms on the virulence of L. monocytogenes. In this study, the growth of L. monocytogenes was evaluated in a single culture or in coculture with L. innocua, Bacillus subtilis, Lactobacillus plantarum, or Pseudomonas aeruginosa in tryptic soy broth (10°C/10 days and 37°C/24 h). Transcriptional levels of 9 key virulence genes (inlA, inlB, inlC, inlJ, sigB, prfA, hly, plcA, and plcB) and invasion efficiency and intracellular growth in Caco-2 cells were determined for L. monocytogenes following growth in mono- or coculture for 3 days at 10°C or 9 h at 37°C. The growth of L. monocytogenes was negatively affected by the presence of L. innocua and B. subtilis, while the effect of cell-to-cell contact on L. monocytogenes growth was dependent on the competing microorganism. Cocultivation affected the in vitro virulence properties of L. monocytogenes in a microorganism-specific manner, with L. innocua mainly enhancing and B. subtilis reducing the invasion of the pathogen in Caco-2 cells. Assessment of the mRNA levels of L. monocytogenes virulence genes in the presence of the four tested bacteria revealed a complex pattern in which the observed up- or downregulation was only partially correlated with growth or in vitro virulence and mainly suggested that L. monocytogenes may display a microorganism-specific transcriptional response. IMPORTANCE Listeria monocytogenes is the etiological agent of the severe foodborne disease listeriosis. Important insight regarding the physiology and the infection biology of this microorganism has been acquired in the past 20 years. However, despite the fact that L. monocytogenes coexists with various microorganisms throughout its life cycle and during transmission from the environment to foods and then to the host, there is still limited knowledge related to the impact of surrounding microorganisms on L. monocytogenes' biological functions. In this study, we showed that L. monocytogenes modulates specific biological activities (i.e., growth and virulence potential) as a response to coexisting microorganisms and differentially alters the expression of virulence-associated genes when confronted with different bacterial genera and species. Our work suggests that the interaction with different bacteria plays a key role in the survival strategies of L. monocytogenes and supports the need to incorporate biotic factors into the research conducted to identify mechanisms deployed by this organism for establishment in different environments.

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Macrophage colony-stimulating factor-induced bone marrow macrophages do not synthesize or release prostaglandin E2

Blood ◽

10.1182/blood.v83.11.3316.bloodjournal83113316 ◽

1994 ◽

Vol 83 (11) ◽

pp. 3316-3323 ◽

Cited By ~ 1

Author(s):

Y Shibata ◽

DR Bjorkman ◽

M Schmidt ◽

Y Oghiso ◽

A Volkman

Keyword(s):

Bone Marrow ◽

Enzyme Activity ◽

Prostaglandin E2 ◽

Bone Marrow Cells ◽

Mrna Levels ◽

Colony Stimulating Factor ◽

Murine Bone Marrow ◽

Gm Csf ◽

Stimulating Factor

Previously, we found that murine bone marrow-derived macrophages (MO) induced in vitro by MO-specific colony-stimulating factor (M-CSF) have little capacity to release prostaglandin E2 (PGE2) and other eicosanoids. This work focused on the functional and transcriptional expression of the key enzymes for the PGE2 synthesis in the MO. Nonadherent bone marrow cells were cultured with RPMI1640 plus 10% fetal bovine serum (FBS) further supplemented with either M-CSF or granulocyte-macrophage (GM)-CSF and interleukin-3 (IL-3). Cellular PGG/H synthase (cyclooxygenase) levels were quantified by cytometric analysis with antibodies specific for the two isozymes of PGG/H synthase (PGG/H synthases 1 and 2). The enzyme activity was monitored by adding exogenous arachidonic acid (AA) substrate to the bone marrow MO cultures and to the cell-free particulate fractions. The levels of PGE2 converted were quantitated by radioimmunoassay (RIA). mRNA levels of the enzymes were detected by Northern blot analysis hybridized with mouse PGG/H synthase cDNA probes, 2.7 kb (PGG/H synthase 1) and 4.2 kb (PGG/H synthase 2). In addition, cellular phospholipase A2 (PLA2) activities were detected with sn-2–14C-arachidonyl phosphatidylcholine as a substrate. Cells proliferating in the presence of GM-CSF and IL-3 for more than 4 days showed significant release of PGE2 (> 7 ng/10(6) cells) when stimulated by AA. These cells also expressed significant amounts of PGG/H synthase 1 protein, its mRNA (2.7 kb) and cellular PLA2. M-CSF-induced MO, in sharp contrast, expressed little PGG/H synthase protein, mRNA, cellular enzyme activity, or PGE2 release, despite comparable levels of cellular PLA2 activity. These data suggest that the capacity of differentiating marrow-derived MO to form PGE2 is growth factor-dependent.

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