Role of K+ Channels in Alveolar Macrophages-Mediated Inflammatory Response upon Anthrax Lethal Toxin Stimulation

ABSTRACT Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (Mφ) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT Mφ sensitivity Kif1C locus to analyze the role of Mφ sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1β occurred only in mice having LT-sensitive Mφ. However, while iNOS knockout C57BL/6J mice having LT-sensitive Mφ were much more susceptible to LT than the knockout mice with LT-resistant Mφ, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between Mφ sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive Mφ and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant Mφ and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires Mφ lysis and while Mφ sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of Mφ sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling Mφ lysis and cytokine response and is independent of Tlr4 function.

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Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy

British Journal of Pharmacology ◽

10.1111/j.1476-5381.2012.02040.x ◽

2012 ◽

Vol 167 (3) ◽

pp. 612-626 ◽

Cited By ~ 10

Author(s):

Machender R Kandadi ◽

Arthur E Frankel ◽

Jun Ren

Keyword(s):

Lethal Toxin ◽

Contractile Dysfunction ◽

Toll Like Receptor ◽

Anthrax Lethal Toxin ◽

Toll Like Receptor 4 ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

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The Role of NF-κB and H3K27me3 Demethylase, Jmjd3, on the Anthrax Lethal Toxin Tolerance of RAW 264.7 Cells

PLoS ONE ◽

10.1371/journal.pone.0009913 ◽

2010 ◽

Vol 5 (3) ◽

pp. e9913 ◽

Cited By ~ 23

Author(s):

Nando Dulal Das ◽

Kyoung Hwa Jung ◽

Young Gyu Chai

Keyword(s):

Lethal Toxin ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Anthrax Lethal Toxin

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Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

Infection and Immunity ◽

10.1128/iai.00275-06 ◽

2006 ◽

Vol 74 (9) ◽

pp. 5029-5034 ◽

Cited By ~ 51

Author(s):

Wilson J. Ribot ◽

Rekha G. Panchal ◽

Katherine C. Brittingham ◽

Gordon Ruthel ◽

Tara A. Kenny ◽

...

Keyword(s):

Immune Responses ◽

Bacillus Anthracis ◽

Nonhuman Primate ◽

Alveolar Macrophages ◽

Lethal Toxin ◽

Innate Immune ◽

Binary Complex ◽

Immune Functions ◽

Anthrax Lethal Toxin ◽

Ames Strain

ABSTRACT Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the binary complex virulence factors produced by B. anthracis, on freshly isolated nonhuman primate AM. Exposure of AM to doses of LT that killed susceptible macrophages had no effect on the viability of AM, despite complete MEK1 cleavage. Intoxicated AM remained fully capable of B. anthracis spore phagocytosis. However, pretreatment of AM with LT resulted in a significant decrease in the clearance of both the Sterne strain and the fully virulent Ames strain of B. anthracis, which may have been a result of impaired AM secretion of proinflammatory cytokines. Our data imply that cytolysis does not correlate with MEK1 cleavage, and this is the first report of LT-mediated impairment of nonhuman primate AM bactericidal activity against B. anthracis.

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Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

BMC Medicine ◽

10.1186/1741-7015-10-134 ◽

2012 ◽

Vol 10 (1) ◽

Cited By ~ 13

Author(s):

Machender R Kandadi ◽

Xuejun Yu ◽

Arthur E Frankel ◽

Jun Ren

Keyword(s):

Oxidative Stress ◽

Lethal Toxin ◽

Contractile Dysfunction ◽

Anthrax Lethal Toxin ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

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PPARs in Alveolar Macrophage Biology

PPAR Research ◽

10.1155/2007/23812 ◽

2007 ◽

Vol 2007 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Monica R. Smith ◽

Theodore J. Standiford ◽

Raju C. Reddy

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Crucial Role ◽

Respiratory Function ◽

Lung Diseases ◽

First Line ◽

Phagocytotic Activity

PPARs, most notably PPAR-γ, play a crucial role in regulating the activation of alveolar macrophages, which in turn occupy a pivotal place in the immune response to pathogens and particulates drawn in with inspired air. In this review, we describe the dual role of the alveolar macrophage as both a first-line defender through its phagocytotic activity and a regulator of the immune response. Depending on its state of activation, the alveolar macrophage may either enhance or suppress different aspects of immune function in the lung. We then review the role of PPAR-γand its ligands in deactivating alveolar macrophages—thus limiting the inflammatory response that, if unchecked, could threaten the essential respiratory function of the alveolus—while upregulating the cell's phagocytotic activity. Finally, we examine the role that inadequate or inappropriate PPAR-γresponses play in specific lung diseases.

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Role of Alveolar Macrophages in the Inflammatory Response After Trauma

Shock ◽

10.1097/shk.0000000000000167 ◽

2014 ◽

Vol 42 (1) ◽

pp. 3-10 ◽

Cited By ~ 34

Author(s):

Ulrike Niesler ◽

Annette Palmer ◽

Peter Radermacher ◽

Markus S. Huber-Lang

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages

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Impact of the FcγII-receptor on quartz uptake and inflammatory response by alveolar macrophages

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00261.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. L1137-L1148 ◽

Cited By ~ 18

Author(s):

Petra Haberzettl ◽

Roel P. F. Schins ◽

Doris Höhr ◽

Verena Wilhelmi ◽

Paul J. A. Borm ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Inhibitory Effect ◽

Small Gtpases ◽

Downstream Signaling ◽

Particle Uptake

The inflammatory response following particle inhalation is described as a key event in the development of lung diseases, e.g., fibrosis and cancer. The essential role of alveolar macrophages (AM) in the pathogenicity of particles through their functions in lung clearance and mediation of inflammation is well known. However, the molecular mechanisms and direct consequences of particle uptake are still unclear. Inhibition of different classic phagocytosis receptors by flow cytometry shows a reduction of the dose-dependent quartz particle (DQ12) uptake in the rat AM cell line NR8383. Thereby the strongest inhibitory effect was observed by blocking the FcγII-receptor (FcγII-R). Fluorescence immunocytochemistry, demonstrating FcγII-R clustering at particle binding sites as well as transmission electron microscopy, visualizing zippering mechanism-like morphological changes, confirmed the role of the FcγII-R in DQ12 phagocytosis. FcγII-R participation in DQ12 uptake was further strengthened by the quartz-induced activation of the Src-kinase Lyn, the phospho-tyrosine kinases Syk (spleen tyrosine kinase) and PI3K (phosphatidylinositol 3-kinase), as shown by Western blotting. Activation of the small GTPases Rac1 and Cdc42, shown by immunoprecipitation, as well as inhibition of tyrosine kinases, GTPases, or Rac1 provided further support for the role of the FcγII-R. Consistent with the uptake results, FcγII-R activation with its specific ligand caused a similar generation of reactive oxygen species and TNF-α release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcγII-R and its downstream signaling cascade in the phagocytosis of quartz particles in AM as well as in the associated generation and release of inflammatory mediators.

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Role of C fibers in the inflammatory response to intratracheal lipopolysaccharide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.271.3.l425 ◽

1996 ◽

Vol 271 (3) ◽

pp. L425-L431 ◽

Cited By ~ 1

Author(s):

N. C. Long ◽

C. W. Frevert ◽

S. A. Shore

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Tumor Necrosis ◽

Pulmonary Inflammation ◽

Intratracheal Instillation ◽

C Fibers ◽

Vehicle Treatment ◽

Necrosis Factor

We proposed that C fibers play a role in mediating the inflammatory response to the intratracheal instillation of lipopolysaccharaide (LPS), a purified form of endotoxin. To test this hypothesis, we compared the inflammatory response to intratracheal LPS (0.1-2.5 mg/kg) in rats whose C fibers had been destroyed by neonatal capsaicin treatment to the response seen in animals that were treated with vehicle. Three hours after the instillation of LPS, we assessed pulmonary inflammation by performing bronchoalveolar lavage (BAL) on the animals. We measured the number of neutrophils, the concentration of protein as an index of vascular permeability, and the concentration of tumor necrosis factor (TNF). Our results indicate that capsaicin treatment resulted in more neutrophils and higher levels of protein and TNF in the BAL fluid in response to intratracheal LPS, compared with vehicle treatment. Using cells from both groups of rats, we also assessed the production of inflammatory mediators by alveolar macrophages incubated with LPS (0.3-30 ng/ml) in vitro. We found a modest increase in the concentration of TNF and nitrite in the supernatant of macrophages collected from capsaicin-treated rats, in comparison with vehicle-treated animals. These results are consistent with the hypothesis that intrinsic differences in the sensitivity of alveolar macrophages of capsaicin and vehicle-treated animals contribute to the greater inflammatory response of capsaicin-treated rat to intratracheal LPS.

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