Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils

Kobayashi, Scott D.; Braughton, Kevin R.; Whitney, Adeline R.; Voyich, Jovanka M.; Schwan, Tom G.; Musser, James M.; DeLeo, Frank R.

doi:10.1073/pnas.1833375100

Cited by 310 publications

(377 citation statements)

References 20 publications

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“…2,16,17 Identifying gene expression that is unique to individual stimuli will reveal potential therapeutic targets that modify specific elements of neutrophil function. To explore the apoptosis-related transcriptional changes that follow PKA activation, an unbiased microarray approach was taken.…”

Section: Resultsmentioning

confidence: 99%

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Prince

Prosseda

Higgins

et al. 2017

Blood

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Key Points• We demonstrate an important role for NR4A receptors in regulating neutrophil lifespan and homeostasis in vitro and in vivo.• These findings may define targets for therapies for diseases driven by defects in neutrophil number and/or survival.The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that PKA activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3. Direct PKA activation by the siteselective PKA agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of PKA, including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a PKA-dependent manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. PKA activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to PKA activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis.

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Section: Resultsmentioning

confidence: 99%

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Prince

Prosseda

Higgins

et al. 2017

Blood

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“…71 During phagocytic interaction with human neutrophils, GAS modulates expression of the core set of PMN genes comprising the common apoptosis program. 64 However, the pathogen also triggers changes in gene expression not observed with other bacteria tested, including repression of genes involved in specific cell survival pathways. 64 Changes in the expression of these genes significantly parallels accelerated PMN apoptosis and host cell lysis (Figure 4).…”

Section: Gas Modulates Human Pmn Gene Expression and Functionmentioning

confidence: 99%

“…However, GAS is relatively resistant to killing by these anti-bacterial components. 53,54,[61][62][63][64] Although progress has been made, the molecular basis for this resistance is incompletely understood. Two recent transcriptome-based studies shed new light on the gene regulation mechanisms used by GAS to avoid destruction by human PMNs.…”

Section: Identification Of a Gas Genetic Program That Protects Againsmentioning

confidence: 99%

“…64,66 -68 This process is linked to the production of NADPH oxidase-derived reactive oxygen species. 69 -72 Using human oligonucleotide microarrays throughout the course of several independent studies, Kobayashi and colleagues 64,67,71 discovered an apoptosis differentiation program in human PMNs that likely facilitates the resolution of infection. The apoptosis differentiation program is comprised of a core set of genes commonly induced or repressed after uptake of bacteria.…”

Section: Gas Modulates Human Pmn Gene Expression and Functionmentioning

confidence: 99%

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Toward a Genome-Wide Systems Biology Analysis of Host-Pathogen Interactions in Group A Streptococcus

Musser

DeLeo

2005

The American Journal of Pathology

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Genome-wide analysis of microbial pathogens and molecular pathogenesis processes has become an area of considerable activity in the last 5 years. These studies have been made possible by several advances, including completion of the human genome sequence, publication of genome sequences for many human pathogens, development of microarray technology and high-throughput proteomics, and maturation of bioinformatics. Despite these advances, relatively little effort has been expended in the bacterial pathogenesis arena to develop and use integrated research platforms in a systems biology approach to enhance our understanding of disease processes. This review discusses progress made in exploiting an integrated genome-wide research platform to gain new knowledge about how the human bacterial pathogen group A Streptococcus causes disease. Results of these studies have provided many new avenues for basic pathogenesis research and translational research focused on development of an efficacious human vaccine and novel therapeutics. One goal in summarizing this line of study is to bring exciting new findings to the attention of the investigative pathology community. In addition, we hope the review will stimulate investigators to consider using analogous approaches for analysis of the molecular pathogenesis of other microbes.

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“…A family of pore-forming bacterial cytotoxins, including those elaborated by the leading pathogens Streptococcus pyogenes, Staphylcoccus aureus, and Listeria monocytogenes are one class of agents triggering cell death phenotypes. For example, S. pyogenes induces rapid, dose-dependent apoptosis of neutrophils [43] and macrophages [44]. This cell death pathway involves apoptotic caspases and requires GAS internalization by the phagocyte.…”

Section: Modulation Of Host Cell Apoptosismentioning

confidence: 99%

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

Silva

Nizet

2009

Apoptosis

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Sepsis is a major health problem and a leading cause of death worldwide. In recent years, a crescendo of attention has been directed to the mechanisms of cell death that develop during this disease, since these are viewed as important contributors to the proinflammatory and antiinflammatory responses associated with poor outcome. Here we discuss mechanisms of cell death evident severe bacterial infection and sepsis including necrosis, apoptosis, pyroptosis, and extracellular trap-associated neutrophil death, with a particular emphasis on lymphocyte apoptosis and its contribution to the immunosuppressed phenotype of late sepsis. Individual bacterial pathogens express virulence factors that modulate cell death pathways and influence the sepsis phenotype. A greater knowledge of cell death pathways in sepsis informs the potential for future therapies designed to ameliorate immune dysfunction in this syndrome.

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Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils

Cited by 310 publications

References 20 publications

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival

Toward a Genome-Wide Systems Biology Analysis of Host-Pathogen Interactions in Group A Streptococcus

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

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