Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2

Lee, Sung Kyun; Kim, Sang Doo; Kook, Minsoo; Lee, Ha Young; Ghim, Jaewang; Choi, Youngwoo; Zabel, Brian A.; Ryu, Sung Ho; Bae, Yoe‐Sik

doi:10.1084/jem.20141813

Cited by 77 publications

(91 citation statements)

References 25 publications

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“…Rac2, PI3K, and CXCR2 are all important in neutrophil activity in both zebrafish and mammals (34,38,(47)(48)(49)(50). Further, the unchanged neutrophil recruitment upon CXCR2 inhibition suggests that neutrophil activation may be an important function of CXCR2.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of studies in mouse and zebrafish suggest that CXCR2 plays a complex time-and organ-specific role in neutrophil recruitment (47,48,51,52). A potential role of CXCR2 in activation is supported by studies showing that CXCR2 activates neutrophil killing by neutrophil extracellular traps (NETs) and is specifically required against C. albicans hyphae (47,49). The recruitment-independent activity of chemokine receptors has also been observed in murine CXCR1 deficiency and may therefore be a widely used potentiator of efficient killing (53).…”

Section: Discussionmentioning

confidence: 99%

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Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

2017

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Candida albicans is a ubiquitous mucosal commensal that is normally prevented from causing acute or chronic invasive disease. Neutrophils contribute to protection in oral infection but exacerbate vulvovaginal candidiasis. To dissect the role of neutrophils during mucosal candidiasis, we took advantage of a new, transparent zebrafish swim bladder infection model. Intravital microscopic tracking of individual animals revealed that the blocking of neutrophil recruitment leads to rapid mortality in this model through faster disease progression. Conversely, artificial recruitment of neutrophils during early infection reduces disease pressure. Noninvasive longitudinal tracking showed that mortality is a consequence of C. albicans breaching the epithelial barrier and invading surrounding tissues. Accordingly, we found that a hyperfilamentous C. albicans strain breaches the epithelial barrier more frequently and causes mortality in immunocompetent zebrafish. A lack of neutrophils at the infection site is associated with less fungusassociated extracellular DNA and less damage to fungal filaments, suggesting that neutrophil extracellular traps help to protect the epithelial barrier from C. albicans breach. We propose a homeostatic model where C. albicans disease pressure is balanced by neutrophil-mediated damage of fungi, maintaining this organism as a commensal while minimizing the risk of damage to host tissue. The unequaled ability to dissect infection dynamics at a high spatiotemporal resolution makes this zebrafish model a unique tool for understanding mucosal host-pathogen interactions.KEYWORDS Candida albicans, mucosal immunity, neutrophils, zebrafish C andida albicans is the most successful commensal fungus at causing opportunistic mucosal and invasive infections (1, 2). The opportunistic nature of C. albicans mucosal infection suggests that there is a constantly challenged impasse between our immune defenses and C. albicans virulence factors (3, 4). Chronic mucocutaneous candidiasis (CMC) is associated with inborn errors of adaptive immune pathways, especially Th17 immunity (5). However, acute oropharyngeal candidiasis (OPC) is more common in neutropenic patients and can result from a multitude of immunesuppressive treatments that affect both innate and adaptive immunity, such as radiation/chemotherapy and corticosteroid or antibiotic use (6, 7).Experimental work in murine models of OPC suggests that C. albicans is kept at bay in mucosal tissues through the action of epithelial cells, neutrophils, and macrophages (8). To protect from mucosal invasion in OPC, neutrophils must be present in the blood, be recruited to the site of infection, and possess a fully functional antimicrobial arsenal (9-12). Neutrophils attack both the yeast and filamentous forms of C. albicans and are associated with vulvovaginal candidiasis (13-15). Counterintuitively, because symptomatic infection is more closely associated with high neutrophil numbers than with the fungal burden, it is believed that neutrophils do more to cause...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

2017

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“…The subsequent GRK phosphorylation of GPCRs on their C‐terminus results in the functional desensitization of the chemokine receptor in a β‐arrestin‐ and clathrin‐dependent manner . The activation of TLR 2, 4 and 9 in response to lipoteichoic acid, LPS and CpG‐oligodeoxynucleotide can also induce the internalization of CXCR2 by up‐regulating GRK2 expression during sepsis in mice . Nitric oxide (NO), which can be produced by numerous cells under the stimulation of inflammatory cytokines and bacterial products in an inducible nitric oxide synthase (iNOS)‐dependent pathway, is of significant importance in the antimicrobial activity of neutrophils , and complete deficiency of this mediator can increase bacterial burden .…”

Section: Effects Of Sepsis On Neutrophilsmentioning

confidence: 99%

Neutrophil dysregulation during sepsis: an overview and update

Shen

Cao

Jiang

et al. 2017

J Cellular Molecular Medi

242

203

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Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis.

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“…Collected peritoneal fluids were diluted to 1:1000 and 1:10,000, plated on tryptic soy agar dishes (Difco Laboratories, Detroit, MI, USA), and incubated for 24 hours at 37°C. Bacterial counts were determined according to a previous report (39).…”

Section: Determination Of Bacterial Countsmentioning

confidence: 99%

Novel CD11b ⁺ Gr-1 ⁺ Sca-1 ⁺ myeloid cells drive mortality in bacterial infection

et al. 2020

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Extreme pathophysiological stressors induce expansion of otherwise infrequent leukocyte populations. Here, we found a previously unidentified CD11b+Gr-1+ myeloid cell population that expresses stem cell antigen-1 (Sca-1) induced upon experimental infection with Staphylococcus aureus. Although CD11b+Gr-1+Sca-1+ cells have impaired migratory capacity and superoxide anion–producing activity, they secrete increased levels of several cytokines and chemokines compared to Sca-1− counterparts. The generation of CD11b+Gr-1+Sca-1+ cells is dependent on IFN-γ in vivo, and in vitro stimulation of bone marrow cells or granulocyte-macrophage progenitors with IFN-γ generated CD11b+Gr-1+Sca-1+ cells. Depletion of CD11b+Gr-1+Sca-1+ cells by administrating anti–Sca-1 antibody strongly increased survival rates in an S. aureus infection model by reducing organ damage and inflammatory cytokines. However, adoptive transfer of CD11b+Gr-1+Sca-1+ cells decreased survival rates by worsening the pathogenesis of S. aureus infection. Together, we found a previously unidentified pathogenic CD11b+Gr-1+Sca-1+ population that plays an essential role in mortality during bacterial infection.

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Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2

Abstract: Lee et al. find that phospholipase D2 deficiency increases survival and decreases organ damage during experimental sepsis in mice which could be reversed with a CXCR2 antagonist. Thus, targeting PLD2 may offer therapeutics for septic patients.

Cited by 77 publications

References 25 publications

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

Neutrophil dysregulation during sepsis: an overview and update

Novel CD11b ⁺ Gr-1 ⁺ Sca-1 ⁺ myeloid cells drive mortality in bacterial infection

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Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2

Abstract: Lee et al. find that phospholipase D2 deficiency increases survival and decreases organ damage during experimental sepsis in mice which could be reversed with a CXCR2 antagonist. Thus, targeting PLD2 may offer therapeutics for septic patients.

Cited by 77 publications

References 25 publications

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

Neutrophil dysregulation during sepsis: an overview and update

Novel CD11b + Gr-1 + Sca-1 + myeloid cells drive mortality in bacterial infection

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Product

Resources

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Novel CD11b ⁺ Gr-1 ⁺ Sca-1 ⁺ myeloid cells drive mortality in bacterial infection