PGE
            <sub>2</sub>
            production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo

Loynes, Catherine A.; Lee, Jou A.; Robertson, Anne L.; Steel, Michael J. G.; Ellett, Felix; Feng, Yi; Levy, Bruce D.; Whyte, Moira K. B.; Renshaw, Stephen A.

doi:10.1126/sciadv.aar8320

Cited by 165 publications

(138 citation statements)

References 70 publications

(100 reference statements)

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“…First, the presence of neutrophils at a wound may be increased in macrophage-deficient larvae, and, as neutrophils can cause tissue damage, an increased presence of neutrophils may be the factor that delays repair and regeneration. This is especially true for experiments with irf8 mutants or morphants that have increased total numbers of neutrophils, but may also occur with other macrophage depletion methods, as macrophages can promote neutrophil resolution from wounds (Tauzin et al, 2014;Loynes et al, 2018). In a blood vessel repair model, more neutrophils were observed at the injury site after macrophage depletion (Gurevich et al, 2018).…”

Section: Macrophages Regulate the Inflammatory Environment At Sterilementioning

confidence: 99%

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Rosowski

2020

Disease Models &Amp; Mechanisms

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The specific roles of the two major innate immune cell typesneutrophils and macrophagesin response to infection and sterile inflammation are areas of great interest. The larval zebrafish model of innate immunity, and the imaging capabilities it provides, is a source of new research and discoveries in this field. Multiple methods have been developed in larval zebrafish to specifically deplete functional macrophages or neutrophils. Each of these has pros and cons, as well as caveats, that often make it difficult to directly compare results from different studies. The purpose of this Review is to (1) explore the pros, cons and caveats of each of these immune cell-depleted models; (2) highlight and place into a broader context recent key findings on the specific functions of innate immune cells using these models; and (3) explore future directions in which immune cell depletion methods are being expanded.

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Section: Macrophages Regulate the Inflammatory Environment At Sterilementioning

confidence: 99%

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Rosowski

2020

Disease Models &Amp; Mechanisms

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“…51 The authors showed that rather than direct membrane contact between neutrophils and macrophages, the prostaglandin E2 released by macrophages is required for induction of the migratory behavior of neutrophils observed in reverse migration. 51 By contrast, in a mouse thermal liver injury model, the depletion of monocytes or macrophages did not affect the clearance of neutrophils from the site of injury, despite the fact that monocytes and macrophages were observed to enter into direct contact with neutrophils during the first 24 h following injury. 52 More research is needed in this nascent field to determine the importance of neutrophil-macrophage crosstalk in reverse migration.…”

Section: Reverse Migrationmentioning

confidence: 99%

Neutrophil–macrophage cooperation and its impact on tissue repair

Bouchery

Harris

2019

Immunol Cell Biol

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Immune cells are rapidly recruited to a site of injury or infection. Although the importance of phagocytic immune cells in clearing bacteria has long been appreciated, the advent of technologies allowing more in‐depth analysis of cellular function, such as intravital microscopy and the use of genetically modified animal models, has allowed much deeper insight into the complex roles of these cells play during tissue repair. Many immune cells contribute to the repair process; however, this review will concentrate on the involvement of the phagocytes, namely macrophages and neutrophils, with a particular focus on our more recent understanding of how interactions between these two cell types impact on the final outcome of tissue repair.

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“…These findings were different to what we had observed in vitro but because this phenotype was phospholipase B1 dependent we reasoned that these inhibitors could be having off target effects on C. neoformans - although C. neoformans does not have a homolog to cyclooxygenase other studies have tried to inhibit eicosanoid production in Cryptococcus using cyclooxygenase inhibitors but their efficacy and target remain uncertain (17,28). To support our pharmacological evidence, we used a CRISPR/Cas9-mediated knockdown of the prostaglandin E 2 synthase gene ( ptges) (29). We used a knockdown of tyrosinase ( tyr ) – a gene involved in the conversion of tyrosine into melanin as a control because tyr −/− crispants are easy to identify because they do not produce any pigment.…”

Section: Resultsmentioning

confidence: 99%

15-keto-prostaglandin E₂activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promoteCryptococcus neoformansgrowth during infection

Evans

Pline

Needs

et al. 2017

Preprint

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Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.Author SummaryCryptococcus neoformans is an opportunistic fungal pathogen that is responsible for significant numbers of deaths in the immunocompromised population worldwide. Here we address whether eicosanoids produced by C. neoformans manipulate host innate immune cells during infection. Cryptococcus neoformans produces several eicosanoids that are notable for their similarity to vertebrate eicosanoids, it is therefore possible that fungal-derived eicosanoids may provoke physiological effects in the host. Using a combination of in vitro and in vivo infection models we identify a specific eicosanoid species - prostaglandin E2 – that is required by C. neoformans for growth during infection. We subsequently show that prostaglandin E2 must be converted to 15-keto-prostaglandin E2 within the host before it has these effects. Furthermore, we find that prostaglandin E2/15-keto-prostaglandin E2 mediated virulence is via activation of host PPAR-γ – an intracellular eicosanoid receptor known to interact with 15-keto-PGE2.

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PGE ₂ production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo

Abstract: Neutrophil removal from inflammatory sites is regulated by lipid mediator signals between macrophages and neutrophils.

Cited by 165 publications

References 70 publications

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Neutrophil–macrophage cooperation and its impact on tissue repair

15-keto-prostaglandin E₂activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promoteCryptococcus neoformansgrowth during infection

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PGE 2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo

Abstract: Neutrophil removal from inflammatory sites is regulated by lipid mediator signals between macrophages and neutrophils.

Cited by 165 publications

References 70 publications

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

Neutrophil–macrophage cooperation and its impact on tissue repair

15-keto-prostaglandin E2activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promoteCryptococcus neoformansgrowth during infection

Contact Info

Product

Resources

About

PGE ₂ production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo

15-keto-prostaglandin E₂activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promoteCryptococcus neoformansgrowth during infection