Prostaglandin E<sub>2</sub> inhibits neutrophil extracellular trap formation through production of cyclic AMP

Shishikura, Kyosuke; Horiuchi, Takahiro; Sakata, Natsumi; Trinh, Duc Anh; Shirakawa, Ryutaro; Kimura, Toshiro; Asada, Yujiro; Horiuchi, Hisanori

doi:10.1111/bph.13373

Cited by 83 publications

(63 citation statements)

References 49 publications

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“…NET formation also occurs during various chronic inflammatory diseases (Kolaczkowska and Kubes, 2013). PGE 2 inhibited NET formation in isolated neutrophils induced by PMA or rapamycin through EP 2 /EP 4 -cAMP receptor signalling (Domingo-Gonzalez et al, 2016;Shishikura et al, 2016), although the extent to which this mechanism operates in vivo remains unknown.…”

Section: Figurementioning

confidence: 99%

Prostaglandin‐cytokine crosstalk in chronic inflammation

Yao

Narumiya

2018

British J Pharmacology

191

136

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Chronic inflammation underlies various debilitating disorders including autoimmune, neurodegenerative, vascular and metabolic diseases as well as cancer, where aberrant activation of the innate and acquired immune systems is frequently seen. Since non‐steroidal anti‐inflammatory drugs exert their effects by inhibiting COX and suppressing PG biosynthesis, PGs have been traditionally thought to function mostly as mediators of acute inflammation. However, an inducible COX isoform, COX‐2, is often highly expressed in tissues of the chronic disorders, suggesting an as yet unidentified role of PGs in chronic inflammation. Recent studies have shown that in addition to their short‐lived actions in acute inflammation, PGs crosstalk with cytokines and amplify the cytokine actions on various types of inflammatory cells and drive pathogenic conversion of these cells by critically regulating their gene expression. One mode of such PG‐mediated amplification is to induce the expression of relevant cytokine receptors, which is typically observed in Th1 cell differentiation and Th17 cell expansion, events leading to chronic immune inflammation. Another mode of amplification is cooperation of PGs with cytokines at the transcription level. Typically, PGs and cytokines synergistically activate NF‐κB to induce the expression of inflammation‐related genes, one being COX‐2 itself, which makes PG‐mediated positive feedback loops. This signalling consequently enhances the expression of various NF‐κB‐induced genes including chemokines to macrophages and neutrophils, which enables sustained infiltration of these cells and further amplifies chronic inflammation. In addition, PGs are also involved in tissue remodelling such as fibrosis and angiogenesis. In this article, we review these findings and discuss their relevance to human diseases.

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Section: Figurementioning

confidence: 99%

Prostaglandin‐cytokine crosstalk in chronic inflammation

Yao

Narumiya

2018

British J Pharmacology

191

136

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“…Small molecule inhibitors of peptidylarginine deiminase inhibit NET generation and have been protective in murine models of lupus and atherosclerosis . Prostaglandin E2 was recently shown to inhibit NET generation . Targeting NETs or specific NET constituents merits further investigation as adjunctive therapies for cancer, initially in tumor‐bearing mice.…”

Section: Future Therapeutic Strategies Targeting Neutrophils In the Tmentioning

confidence: 99%

“…[186][187][188] Prostaglandin E2 was recently shown to inhibit NET generation. 189 Targeting NETs or specific NET constituents merits further investigation as adjunctive therapies for cancer, initially in tumor-bearing mice.…”

Section: Future Therapeutic Strategies Targeting Neutrophils In Thementioning

confidence: 99%

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Singel

Segal

2016

Immunological Reviews

156

130

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Summary Neutrophils are the first responders to infection and injury and are critical for antimicrobial host defense. Through the generation of reactive oxidants, activation of granular constituents and neutrophil extracellular traps, neutrophils target microbes and prevent their dissemination. While these pathways are beneficial in the context of trauma and infection, their off-target effects in the context of tumor are variable. Tumor-derived factors have been shown to reprogram the marrow, skewing toward the expansion of myelopoiesis. This can result in stimulation of both neutrophilic leukocytosis and the release of immature granulocytic populations that accumulate in circulation and in the tumor microenvironment. While activated neutrophils have been shown to kill tumor cells, there is growing evidence for neutrophil activation driving tumor progression and metastasis through a number of pathways, including stimulation of thrombosis and angiogenesis, stromal remodeling, and impairment of T cell-dependent anti-tumor immunity. There is also growing appreciation of neutrophil heterogeneity in cancer, with distinct neutrophil populations promoting cancer control or progression. In addition to the effects of tumor on neutrophil responses, anti-neoplastic treatment, including surgery, chemotherapy, and growth factors, can influence neutrophil responses. Future directions for research are expected to result in more mechanistic knowledge of neutrophil biology in the tumor microenvironment that may be exploited as prognostic biomarkers and therapeutic targets.

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“…Similar to other cell types, cAMP acts as a key second messenger in the immune system, and in fact, the targeting of the cAMP pathway is widely exploited by the nervous and endocrine systems to modulate the immune response [32][33][34]. cAMP has an overall inhibitory effect on both innate and adaptive immune cell types, including neutrophils [35], macrophages [36], and T and B lymphocytes [37,38]. Prolonged elevation of the intracellular cAMP concentration leads to inhibition of proinflammatory cytokine production [39], macrophage phagocytosis [40], NK cell-mediated cytotoxicity [41], and neutrophil chemotaxis [42].…”

Section: Camp Signaling In T Cell Activationmentioning

confidence: 99%

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

Arumugham

Baldari

2017

Journal of Leukocyte Biology

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T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation.

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Prostaglandin E₂ inhibits neutrophil extracellular trap formation through production of cyclic AMP

Cited by 83 publications

References 49 publications

Prostaglandin‐cytokine crosstalk in chronic inflammation

Prostaglandin‐cytokine crosstalk in chronic inflammation

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

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Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP

Cited by 83 publications

References 49 publications

Prostaglandin‐cytokine crosstalk in chronic inflammation

Prostaglandin‐cytokine crosstalk in chronic inflammation

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

cAMP: a multifaceted modulator of immune synapse assembly and T cell activation

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Prostaglandin E₂ inhibits neutrophil extracellular trap formation through production of cyclic AMP