Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

Balamayooran, Gayathriy; Batra, Sanjay; Fessler, Michael B.; Happel, Kyle I.; Jeyaseelan, Samithamby

doi:10.1165/rcmb.2009-0047tr

Cited by 140 publications

(142 citation statements)

References 146 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…Neutrophil numbers in the bronchoalveolar lavage fluid (BALF) were significantly less in MyD88-deficient (Myd88 2/2 ) mice compared with WT mice (Table 3), consistent with the previously described role of MyD88 in regulating neutrophil recruitment during pulmonary inflammation (34,35). The percentage of IFN-g1 neutrophils and the intensity of IFN-g staining in neutrophils in the BALF and lung tissue after lavage were significantly less in Myd88 2/2 mice, indicating a role for MyD88 in mediating IFN-g production by neutrophils ( Table 3).…”

Section: Myd88 But Not Trif Regulate Ifn-g Productionsupporting

confidence: 87%

See 1 more Smart Citation

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Gomez

Yamada

Martin

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Bacterial pneumonia is a common public health problem associated with significant mortality, morbidity, and cost. Neutrophils are usually the earliest leukocytes to respond to bacteria in the lungs. Neutrophils rapidly sequester in the pulmonary microvasculature and migrate into the lung parenchyma and alveolar spaces, where they perform numerous effector functions for host defense. Previous studies showed that migrated neutrophils produce IFN-g early during pneumonia induced by Streptococcus pneumoniae and that early production of IFN-g regulates bacterial clearance. IFN-g production by neutrophils requires Rac2, Hck/Lyn/Fgr Src family tyrosine kinases, and NADPH oxidase. Our current studies examined the mechanisms that regulate IFN-g production by lung neutrophils during acute S. pneumoniae pneumonia in mice and its function. We demonstrate that IFN-g production by neutrophils is a tightly regulated process that does not require IL-12. The adaptor molecule MyD88 is critical for IFN-g production by neutrophils. The guanine nucleotide exchange factor CalDAG-GEFI modulates IFN-g production. The CD11/CD18 complex, CD44, Toll-like receptors 2 and 4, TRIF, and Nrf2 are not required for IFN-g production by neutrophils. The recently described neutrophil-dendritic cell hybrid cell, identified by its expression of Ly6G and CD11c, is present at low numbers in pneumonic lungs and is not a source of IFN-g. IFN-g produced by neutrophils early during acute S. pneumoniae pneumonia induces transcription of target genes in the lungs, which are critical for host defense. These studies underline the complexity of the neutrophil responses during pneumonia in the acute inflammatory response and in subsequent resolution or initiation of immune responses.

show abstract

Section: Myd88 But Not Trif Regulate Ifn-g Productionsupporting

confidence: 87%

“…MyD88 regulates neutrophil recruitment to the lung during bacterial pneumonia (34,35). TRIF is critical for host responses in pneumonias caused by the gram-negative organisms E. coli (36), Klebsiella pneumoniae (37), and P. aeruginosa (38).…”

Section: Cells (5-7)mentioning

confidence: 99%

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Gomez

Yamada

Martin

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…During pneumococcal pneumonia, there is persistent infiltration of inflammatory immune cells in the lungs that could themselves produce DNA-damaging RONS (6)(7)(8). Hence, inflammation-driven collateral damage to pulmonary cell DNA is plausible during S. pneumoniae infection.…”

Section: S Pneumoniae Induces Dna Damage Responses In Alveolar Epithmentioning

confidence: 99%

“…S. pneumoniae is known to induce a robust inflammatory response at the site of infection that culminates with infiltration and accumulation of inflammatory cells including neutrophils and macrophages (6)(7)(8).…”

mentioning

confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

102

View full text Add to dashboard Cite

Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H 2 O 2 , plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H 2 O 2 , greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H 2 O 2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniaeinduced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.DNA damage | Streptococcus pneumoniae | hydrogen peroxide | γH2AX | Ku80

show abstract

“…Overall, gene expression levels of TLR2 were higher than those of TLR4, regardless of the bacterial species. It is possible that TLR2 also recognizes bacterial lipid and carbohydrate compounds, including lipoteichoic acid and lipoproteins (33). LPS-binding protein (LBP) and CD14 are involved in responses to LPS.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of TREM1 Gene Expression in Circulating Polymorphonuclear Leukocytes and Its Inverse Correlation with the Severity of Pathophysiological Conditions in Patients with Acute Bacterial Infections

et al. 2012

View full text Add to dashboard Cite

SUMMARY:During bacterial infection, activated polymorphonuclear leukocytes (PMNs) often cause inflammation and organ dysfunction in severely ill patients. Gene expression was analyzed in circulating PMNs isolated from these patients to determine the distinct expression profile. We focused on immunomodulatory genes, such as those for pattern recognition receptors, inflammatory cytokines, PMN surface antigens, and myeloid cell receptors in PMNs. Gene expression in 23 patients (12 with pneumonia and 11 with sepsis) were analyzed using quantitative real-time polymerase chain reaction. The mRNA levels of TLR2 (20/23 cases) and CD14 (18/23 cases) were upregulated in the PMNs of patients when compared with healthy subjects. The mRNA expression levels of TLR4 (16/23 cases) and IL6 (16/23 cases) were downregulated in patients' PMNs, and of TNFA (16/23 cases) were upregulated in these cells. Although mRNA levels of IL8RA (15/23 cases) were downregulated in PMNs, MAC-1 mRNA levels (14/23 cases) were upregulated in the same cells. Copies of the TREM1 transcript were 0.7-to 2.1-fold higher in patients with moderate pneumonia than in the healthy subjects; the average fold change was 1.1. The mRNA levels were 0.3-fold lower in the patients with severe pneumonia and sepsis than in the healthy subjects. In conclusion, the downregulation of TREM1 expression in PMNs is associated with the severity of the pathophysiological conditions and may be used as a surrogate marker of acute bacterial infections.

show abstract

Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

Cited by 140 publications

References 146 publications

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Mechanisms of Interferon-γ Production by Neutrophils and Its Function duringStreptococcus pneumoniaePneumonia

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Evaluation of TREM1 Gene Expression in Circulating Polymorphonuclear Leukocytes and Its Inverse Correlation with the Severity of Pathophysiological Conditions in Patients with Acute Bacterial Infections

Contact Info

Product

Resources

About