Inhibition of nitric oxide synthase (NOS) aggravates <i>Staphylococcus aureus</i> septicaemia and septic arthritis

Sakiniene, Egidija; Bremell, Tomas; Tarkowski, Andrzej

doi:10.1046/j.1365-2249.1997.4431456.x

Cited by 47 publications

(14 citation statements)

References 29 publications

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“…1D). In addition to cytokines, we also looked at the induction of nitric oxide (NO) which has been shown to play a role in killing of S. aureus in mice (19, 20). Previous work has indicated that for optimal NO production BMDM need to be primed with IFN-γ (21), so we assessed NO in BMDM that were either unprimed or primed with IFN-γ for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

Phagosomal Degradation Increases TLR Access to Bacterial Ligands and Enhances Macrophage Sensitivity to Bacteria

Wolf

Arruda

Reyes

et al. 2011

The Journal of Immunology

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Signaling by innate immune receptors initiates and orchestrates the overall immune responses to infection. Macrophage receptors recognizing pathogens can be broadly grouped into surface receptors and receptors restricted to intracellular compartments, such as phagosomes and the cytoplasm. There is an expectation that ingestion and degradation of microorganisms by phagocytes contributes to activation of intracellular innate receptors, although direct demonstrations of this are rare and many model ligands are studied in soluble form, outside of their microbial context. By comparing a wild-type strain of Staphylococcus aureus and a lysozyme-sensitive mutant, we have been able to directly address the role of degradation of live bacteria by mouse macrophages in determining the overall innate cellular inflammatory response. Our investigations revealed a biphasic response to S. aureus that consisted of an initial signal resulting from the engagement of surface TLR2, followed by a later, second wave on inflammatory gene induction. This second wave of inflammatory signaling was dependent on and correlated with the timing of bacterial degradation in phagosomes. We found that TLR2 signaling followed by TLR2/TLR9 signaling enhanced sensitivity to small numbers of bacteria. We further found that treating wild-type bacteria with the peptidoglycan synthesis-inhibiting antibiotic vancomycin made S. aureus more susceptible to degradation and resulted in increased inflammatory responses, similar to those observed for mutant degradation-sensitive bacteria.

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Section: Resultsmentioning

confidence: 99%

Phagosomal Degradation Increases TLR Access to Bacterial Ligands and Enhances Macrophage Sensitivity to Bacteria

Wolf

Arruda

Reyes

et al. 2011

The Journal of Immunology

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“…aureus effectively triggers PHOX activity (73) and, depending on the context, is a potent inducer of NOS2 (17). In vivo, mice deficient for either PHOX or NOS2 have an increased susceptibility to S. aureus infections (52,69,70). Macrophages from mice with an individual knockout of the PHOX or NOS2 gene showed an unaltered ability to kill S. aureus in vitro compared to WT M (42), whereas neutrophils from PHOX-deficient mice were ineffective in killing S. aureus (23,34,62).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Mediated Impairment of the Mitochondrial Respiratory Chain Inhibits the Bactericidal Activity of Macrophages

et al. 2012

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eIn infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (M) to kill Escherichia coli or Staphylococcus aureus in a hypoxic microenvironment. Oxygen restriction did not promote intracellular bacterial growth but did impair the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates. Experiments with phagocyte NADPH oxidase (PHOX) and inducible NO synthase (NOS2) double-deficient M revealed that in E. colior S. aureus-infected cells the reduced antibacterial activity during hypoxia was either entirely or partially independent of the diminished PHOX and NOS2 activity. Hypoxia impaired the mitochondrial activity of infected M. Inhibition of the mitochondrial respiratory chain activity during normoxia (using rotenone or antimycin A) completely or partially mimicked the defective antibacterial activity observed in hypoxic E. coli-or S. aureus-infected wild-type M, respectively. Accordingly, inhibition of the respiratory chain of S. aureus-infected, normoxic PHOX ؊/؊ NOS2 ؊/؊ M further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX ؊/؊ NOS2 ؊/؊ M cultures. Our data demonstrate that the reduced killing of S. aureus or E. coli during hypoxia is not simply due to a lack of PHOX and NOS2 activity but partially or completely results from an impaired mitochondrial antibacterial effector function. Since pharmacological inhibition of the respiratory chain raised the generation of ROI but nevertheless phenocopied the effect of hypoxia, ROI can be excluded as the mechanism underlying the antimicrobial activity of mitochondria.

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“…Mice deficient in iNOS show increased susceptibility to L. monocytogenes (20,38). iNOS deficiency is also associated with increased mortality from S. aureus infection (39,40). However, the biology of NO is complicated.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting Enzyme Overexpression in Mouse Myelomonocytic Cells Augments Resistance to Listeria and Methicillin-resistant Staphylococcus aureus

Okwan-Duodu

Datta

Shen

et al. 2010

Journal of Biological Chemistry

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Gene targeting in ES cells was used to substitute control of angiotensin converting enzyme (ACE) expression from the endogenous promoter to the mouse c-fms promoter. The result is an animal model called ACE 10/10 in which ACE is overexpressed by monocytes, macrophages, and other myelomonocytic lineage cells. To study the immune response of these mice to bacterial infection, we challenged them with Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA). ACE 10/10 mice have a significantly enhanced immune response to both bacteria in vivo and in vitro. For example, 5 days after Listeria infection, the spleen and liver of ACE 10/10 mice had 8.0-and 5.2-fold less bacteria than wild type mice (WT). In a model of MRSA skin infection, ACE 10/10 mice had 50-fold less bacteria than WT mice. Histologic examination showed a prominent infiltrate of ACE-positive mononuclear cells in the skin lesions from ACE 10/10. Increased bacterial resistance in ACE 10/10 is directly due to overexpression of ACE, as it is eliminated by an ACE inhibitor. Critical to increased immunity in ACE 10/10 is the overexpression of iNOS and reactive nitrogen intermediates, as inhibition of iNOS by the inhibitor 1400W eliminated all in vitro and in vivo differences in innate bacterial resistance between ACE 10/10 and WT mice. Increased resistance to MRSA was transferable by bone marrow transplantation. The overexpression of ACE and iNOS by myelomonocytic cells substantially boosts innate immunity and may represent a new means to address serious bacterial infections. The classical renin-angiotensin system (RAS)2 is a complex cascade of enzymes and peptides associated with the regulation of blood pressure (1). RAS regulates production of the vasoconstrictor angiotensin II from angiotensinogen via sequential catalysis by renin and angiotensin-converting enzyme (ACE). Although renin is precise in substrate specificity, ACE is a somewhat promiscuous peptidase that cleaves angiotensin I, substance P, AcSDKP, ␤-endorphins, and several other physiologic peptides. Because ACE has a variety of substrates, it may affect several physiologic and pathologic processes such as hematopoiesis, fertility, atherosclerosis, multiple sclerosis, and inflammation (2-5).Several groups have presented evidence highlighting diverse roles for ACE and RAS in the immune response, including production of reactive oxygen species by angiotensin II (6 -8). Recently, Platten et al. (9) showed that RAS plays a major role in autoimmunity, as indicated by their analysis of multiple sclerosis and experimental autoimmune encephalitis. Studies have also found a role for RAS in the recruitment of inflammatory cells into tissues through the regulation of adhesion molecules and chemokines by resident inflammatory cells (7). ACE regulates bradykinin, which is critical for dendritic cell maturation and TH1 cell development during Trypanosoma cruzi infection (10). Clinically, ACE is a useful marker for several cytokine-mediated inflammatory diseases (11). Our group has recen...

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Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis

Cited by 47 publications

References 29 publications

Phagosomal Degradation Increases TLR Access to Bacterial Ligands and Enhances Macrophage Sensitivity to Bacteria

Phagosomal Degradation Increases TLR Access to Bacterial Ligands and Enhances Macrophage Sensitivity to Bacteria

Hypoxia-Mediated Impairment of the Mitochondrial Respiratory Chain Inhibits the Bactericidal Activity of Macrophages

Angiotensin-converting Enzyme Overexpression in Mouse Myelomonocytic Cells Augments Resistance to Listeria and Methicillin-resistant Staphylococcus aureus

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