PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness

Rastogi, Shruti; Willmes, Diana M.; Nassiri, Maria; Babina, Magda; Worm, Margitta

doi:10.1016/j.jaci.2020.03.046

Cited by 37 publications

(30 citation statements)

References 77 publications

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“…Ado, adenosine; green arrows, increase; red arrows, decrease. *Evidence based on references ( 23 , 26 , 28 , 29 , 38 , 39 , 41 , 50 , 57 – 59 , 66 , 67 ).…”

Section: Discussionmentioning

confidence: 99%

“…Particularly misoprostol, a PGE 1 analog, has shown to suppress symptoms in wheat-dependent exercise-induced anaphylaxis and IgE-mediated histamine release in both allergic rhinitis and healthy individuals ( 35 – 37 ). Rastogi et al ( 38 ) have shown that patients with hymenoptera anaphylaxis had lower baseline PGE 2 serum levels, suggesting that PGE 2 may protect from anaphylaxis. Conversely, a very recent publication of Muñoz-Cano et al ( 39 ) did not find any differences in plasma PGE 2 at baseline in a series of FAn patients.…”

Section: Exercisementioning

confidence: 99%

“…Finally, several authors have demonstrated that PGE 2 prevents MC degranulation when acting through EP 2 and induces a pro-inflammatory response when signaling through EP 3 ( 18 , 32 , 53 ). Very recently, Rastogi et al ( 38 ) have shown that anaphylaxis in mice can be prevented by blocking PGE 2 degradation. They also showed that MC IgE-mediated degranulation is suppressed by PGE 2 through EP 4 in mouse MC and through both EP 2 and EP 4 ligation in human skin MC.…”

Section: Nsaidsmentioning

confidence: 99%

See 2 more Smart Citations

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

et al. 2021

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Cofactors may explain why in some cases food ingestion leads to anaphylaxis while in others elicits a milder reaction or tolerance. With cofactors, reactions become more severe and/or have a lower allergen threshold. Cofactors are present in up to 58% of food anaphylaxis (FAn). Exercise, NSAIDs, and alcohol are the most frequently described, although the underlying mechanisms are poorly known. Several hypotheses have suggested the influence of these cofactors on basophils and mast cells (MCs). Exercise has been suggested to enhance MC activation by increasing plasma osmolarity, redistributing blood flow, and activating adenosine and eicosanoid metabolism. NSAIDs’ cofactor effect has been related with cyclooxygenase inhibition and therefore, prostaglandin E2 (PGE2) production. Indeed, overexpression of adenosine receptor 3 (A3) gene has been described in NSAID-dependent FAn; A3 activation potentiates FcϵRI-induced MC degranulation. Finally, alcohol has been related with an increase of histamine levels by inhibition of diamino oxidase (DAO) and also with and increase of extracellular adenosine by inhibition of its uptake. However, most of these mechanisms have limited evidence, and further studies are urgently needed. In conclusion, the study of the immune-related mechanisms involved in food allergic reactions enhanced by cofactors is of the utmost interest. This knowledge will help to design both tailored treatments and prophylactic strategies that, nowadays, are non-existent.

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“…Ado, adenosine; green arrows, increase; red arrows, decrease. *Evidence based on references ( 23 , 26 , 28 , 29 , 38 , 39 , 41 , 50 , 57 – 59 , 66 , 67 ).…”

Section: Discussionmentioning

confidence: 99%

Section: Exercisementioning

confidence: 99%

Section: Nsaidsmentioning

confidence: 99%

See 1 more Smart Citation

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

et al. 2021

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“… 18 Lower levels of PGE2 have been linked with MC hyperresponsiveness. 19 Furthermore, transgenic mPGES1 (-/-) knockout mice are used as an animal model to study AERD, further highlighting the importance of PGE2 in the pathogenesis of this disease. 20 However, the reasons underlying the dysregulation of PGE2 in AERD are yet to be fully described.…”

Section: Pathogenesis Of MC Activation In Aerdmentioning

confidence: 99%

<p>The Role of Mast Cells in Aspirin-Exacerbated Respiratory Disease (AERD) Pathogenesis: Implications for Future Therapeutics</p>

Kuruvilla

Vanijcharoenkarn

Levy

2020

JAA

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Mast cells (MC) have recently been demonstrated to play an integral role in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). When activated, MCs release pre-formed granules of many pro-inflammatory mediators, including histamine, serotonin, and various chemokines and cytokines including tumor necrosis factor (TNF)-α, interferon ɣ (IFN ɣ), macrophage inhibitory factor, transforming growth factor, interleukin (IL) 1, 3-6, 9, 10, 13 and 16. These mediators promote inflammation in AERD by recruiting or activating a network of cells involved in acute and chronic inflammatory pathways, such as endothelial, epithelial, stromal, and other immune cells. Several studies have implicated multifactorial pathways for MC activation in AERD beyond classical IgE mediated mechanisms. The elucidation of these complex networks therefore represents important targets for innovative patient therapeutics. This review summarizes classic and alternative pathways of MC activation in AERD with a special focus in relation to new and emerging treatment strategies.

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“…MCs are rich in histamine-and leukotriene-containing granules however, and thus are poised to rapidly regulate the local tissue microenvironment. Moreover, leukotriene B4 has been hypothesized to promote HSPC differentiation at the expense of self-renewal 29 , and PGE2 suppresses MC degranulation in anaphylaxis 51 . Increased splenic myelopoiesis and thrombopoiesis have also been observed in MC deficient mice 52 .…”

Section: -Pgdh Localization and Enzymatic Activity Is Conserved In mentioning

confidence: 99%

15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

Smith

Dawson

Christo

et al. 2020

Preprint

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The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.

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PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness

Cited by 37 publications

References 77 publications

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

<p>The Role of Mast Cells in Aspirin-Exacerbated Respiratory Disease (AERD) Pathogenesis: Implications for Future Therapeutics</p>

15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration

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