The roles of NADPH oxidase in modulating neutrophil effector responses

Zeng, Melody Y.; Miralda, Irina; Armstrong, Cortney L.; Uriarte, Silvia M.; Bagaitkar, Juhi

doi:10.1111/omi.12252

Cited by 100 publications

(87 citation statements)

References 127 publications

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“…NADPH oxidase is a major source of ROS in PMNs. 64 However, when we used DPI to inhibit NADPH oxidase, we saw no effect on bacterial killing by WT…”

Section: Discussionmentioning

confidence: 92%

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Siwapornchai

Lee

Tchalla

et al. 2020

Journal of Leukocyte Biology

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Polymorphonuclear leukocytes (PMNs) are crucial for initial control of Streptococcus pneumoniae (pneumococcus) lung infection; however, as the infection progresses their persistence in the lungs becomes detrimental. Here we explored why the antimicrobial efficacy of PMNs declines over the course of infection. We found that the progressive inability of PMNs to control infection correlated with phenotypic differences characterized by a decrease in CD73 expression, an enzyme required for production of extracellular adenosine (EAD). EAD production by CD73 was crucial for the ability of both murine and human PMNs to kill S. pneumoniae. In exploring the mechanisms by which CD73 controlled PMN function, we found that CD73 mediated its antimicrobial activity by inhibiting IL‐10 production. PMNs from wild‐type mice did not increase IL‐10 production in response to S. pneumoniae; however, CD73−/− PMNs up‐regulated IL‐10 production upon pneumococcal infection in vitro and during lung challenge. IL‐10 inhibited the ability of WT PMNs to kill pneumococci. Conversely, blocking IL‐10 boosted the bactericidal activity of CD73−/− PMNs as well as host resistance of CD73−/− mice to pneumococcal pneumonia. CD73/IL‐10 did not affect apoptosis, bacterial uptake, and intracellular killing or production of antimicrobial neutrophil elastase and myeloperoxidase. Rather, inhibition of IL‐10 production by CD73 was important for optimal reactive oxygen species (ROS) production by PMNs. ROS contributed to PMN antimicrobial function as their removal or detoxification impaired the ability of PMNs to efficiently kill S. pneumoniae. This study demonstrates that CD73 controls PMN antimicrobial phenotype during S. pneumoniae infection.

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“…NADPH oxidase is a major source of ROS in PMNs. 64 However, when we used DPI to inhibit NADPH oxidase, we saw no effect on bacterial killing by WT…”

Section: Discussionmentioning

confidence: 92%

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Siwapornchai

Lee

Tchalla

et al. 2020

Journal of Leukocyte Biology

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“…Neutrophils migrate from the circulation to sites of infection, where they display several antimicrobial mechanisms against a broad spectrum of bacteria, fungi, and protozoa 1 . Among these mechanisms, degranulation, 89,90 production of ROS, 91 phagocytosis, 9 and formation of NET 92 are the most important (Fig. 7).…”

Section: Antimicrobial Mechanisms Of Neutrophilsmentioning

confidence: 99%

Neutrophils at the crossroads of innate and adaptive immunity

Rosales

2020

Journal of Leukocyte Biology

215

184

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Neutrophils are the most abundant leukocytes in blood. From the circulation, they are quickly mobilized to sites of inflammation and/or infection. At the affected tissues, neutrophils display an impressive array of antimicrobial functions, including degranulation, production of reactive oxygen species (ROS), phagocytosis, and formation of neutrophil extracellular traps (NET). Because neutrophils are the first type of leukocytes to arrive at affected tissues and display potent microbicidal functions, they have been classically viewed as the first line of defense. In this view, neutrophils only destroy invading pathogens and then quietly die at the site of infection. However, in the last decade it has become increasingly evident that neutrophils are much more complex cells having not only effector functions in the innate immune response, but also the capacity of modulating the adaptive immune response, via direct interaction with, or by producing cytokines that affect dendritic cells and lymphocytes. In addition, neutrophil heterogeneity with clear different functional phenotypes has been recently described particularly in cancer and inflammation. This review provides an overview on the life of a neutrophil describing its beginnings, lifespan, and their principal functions in innate and adaptive immunity. Also, neutrophil heterogeneity and our current understanding of neutrophil contributions to health and disease are discussed.

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“…They involve activation of multi-subunit enzymatic cascades (e.g. NADPH oxidases), which produce reactive oxygen species (ROS) and reactive nitrogen intermediates [18]. Future investigations into the precise role for neutrophils and fMLP pathway, the Rho family GTPases, and their inhibitors RhoGDI during oxidative stress in fatal outcomes may lead to future therapies search that would balance intracellular production of reactive oxygen species [19].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Biomarker Pathways Associated with Death in HIV-infected Patients with Cryptococcal Meningitis

Louis

Musubire

Meya

et al. 2020

Preprint

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Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with, or, predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing (COAT) Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: 1) no C-IRIS or Death; 2) C-IRIS survivors; 3) fatal C-IRIS; 4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflect the severity of inflammation and systemic oxidative stress. Those who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. The Partial Least Squares model estimated above mentioned pathways as predictors of fatal outcome.Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.

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The roles of NADPH oxidase in modulating neutrophil effector responses

Cited by 100 publications

References 127 publications

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Neutrophils at the crossroads of innate and adaptive immunity

Transcriptomic Biomarker Pathways Associated with Death in HIV-infected Patients with Cryptococcal Meningitis

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