Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Pace, Simona; Rossi, Antonietta; Krauth, Verena; Dehm, Friederike; Troisi, Fabiana; Bilancia, Rossella; Weinigel, Christina; Rummler, Silke; Werz, Oliver; Sautebin, Lidia

doi:10.1038/s41598-017-03696-8

Cited by 71 publications

(56 citation statements)

References 38 publications

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“…Very recently, it was discovered that microglial response to environmental challenges is sex-specific [ 57 ]. There are also differences between male and female in the quantity and function of neutrophils and monocytes [ 58 – 61 ]. Further, inflammatory responses and injury outcome after neonatal HI have been reported to diverge according to gender, with enhanced inflammation, microglia activation and monocyte infiltration in males compared to females [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Peripheral myeloid cells contribute to brain injury in male neonatal mice

Smith

Mottahedin

Svedin

et al. 2018

J Neuroinflammation

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BackgroundNeonatal brain injury is increasingly understood to be linked to inflammatory processes that involve specialised CNS and peripheral immune interactions. However, the role of peripheral myeloid cells in neonatal hypoxic-ischemic (HI) brain injury remains to be fully investigated.MethodsWe employed the Lys-EGFP-ki mouse that allows enhanced green fluorescent protein (EGFP)-positive mature myeloid cells of peripheral origin to be easily identified in the CNS. Using both flow cytometry and confocal microscopy, we investigated the accumulation of total EGFP+ myeloid cells and myeloid cell subtypes: inflammatory monocytes, resident monocytes and granulocytes, in the CNS for several weeks following induction of cerebral HI in postnatal day 9 mice. We used antibody treatment to curb brain infiltration of myeloid cells and subsequently evaluated HI-induced brain injury.ResultsWe demonstrate a temporally biphasic pattern of inflammatory monocyte and granulocyte infiltration, characterised by peak infiltration at 1 day and 7 days after hypoxia-ischemia. This occurs against a backdrop of continuous low-level resident monocyte infiltration. Antibody-mediated depletion of circulating myeloid cells reduced immune cell accumulation in the brain and reduced neuronal loss in male but not female mice.ConclusionThis study offers new insight into sex-dependent central-peripheral immune communication following neonatal brain injury and merits renewed interest in the roles of granulocytes and monocytes in lesion development.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1344-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Peripheral myeloid cells contribute to brain injury in male neonatal mice

Smith

Mottahedin

Svedin

et al. 2018

J Neuroinflammation

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“…There are too few data for molecular mechanisms consideration, but an interconnection is promising. The sex difference in the basal levels of PGE 2 and 6-keto-PGF 1α , and the prostaglandins release under LPS stimulation were shown for human neutrophils [ 2 ]. It is noteworthy that male neutrophils have initially higher levels of both PGs, and this difference remains after LPS stimulation [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

“…The sex difference in the basal levels of PGE 2 and 6-keto-PGF 1α , and the prostaglandins release under LPS stimulation were shown for human neutrophils [ 2 ]. It is noteworthy that male neutrophils have initially higher levels of both PGs, and this difference remains after LPS stimulation [ 2 ]. The molecular mechanisms and biological significance for this discrepancy remains a matter of future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Sex-dependent variation in the sensitivity of humans to some diseases has been known for a long time (see for reviews [ 1 , 2 , 3 , 4 ]), although, in experimental and clinical studies, the sex of subjects is still rarely taken into account. Only recently within the context of ideas of personalized medicine have researchers focused on identifying the molecular differences between men and women’s responses to external environmental pollutants, pro-inflammatory stimuli, and pharmaceuticals [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Sex-Mediated Differences in LPS Induced Alterations of TNFα, IL-10 Expression, and Prostaglandin Synthesis in Primary Astrocytes

Chistyakov

Azbukina

Astakhova

et al. 2018

IJMS

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Although many neurological and psychiatric disorders reveal clear sex-dependent variations, the molecular mechanism of this process is not clear enough. Astrocytes are involved in the response of neural tissue to injury and inflammation, produce steroid hormones, and sense steroid presence. To explore the hypothesis that astrocytes may participate in sex-mediated differences of inflammatory responses, we have examined whether male and female primary rat astrocytes show different responses to lipopolysaccharide (LPS) as a toll-like receptor 4 (TLR4) agonist. Levels of mRNA and proteins of tumor necrosis factor alpha (TNFα), interleukin-10 (IL-10), and cyclooxygenase (COX)-2 were assessed using qPCR, immunoblotting, and ELISA. UPLC-MS/MS was used to detect prostaglandins (PGs). LPS stimulation resulted in different levels of cytokine production; more TNFα and less IL-10 were produced in female cells compared with male astrocytes. Although the levels of the COX-2 expression were not altered, LPS significantly induced the synthesis of PGs with notable sex-related differences. PGE2 and PGD2 were less and 6-keto-PGF1α was more upregulated in female astrocytes, and TXB2 had similar levels in cells obtained from males and females. Trilostane, an inhibitor of 3β-Hydroxysteroid dehydrogenase (3β-HSD), inhibited the LPS-induced TNFα production and the release of PGE2, PGD2, and 6-keto-PGF1α in female astrocytes. Thus, male and female astrocytes differentially respond to inflammatory challenges on the level of production of cytokines and steroid hormones. Sex-mediated differences in pro- and anti-inflammatory responses should be taken into consideration for the effective treatment of disorders with neuroinflammation.

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“…It has earlier been noticed that the severity and course of inflammatory process differ between women and men. Simona Pace and colleagues (Pace et al, 2017) found that freshly isolated and immediately LPS stimulated human neutrophils from males produced more PGE2 than cells from females and that this might be caused by increased COX-2 expression and by shunting phenomena due to suppressed leukotrienes formation. They conclude that the observed sex-difference might help to explain, at least in part, the sex dimorphism in innate immune disorders such as sepsis and post-surgery infections.…”

Section: Linking Covid-19 Clinical Observations and Pge2mentioning

confidence: 99%

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Smeitink¹,

Jiang²,

Pecheritsyna³

et al. 2020

Preprint

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With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

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Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Cited by 71 publications

References 38 publications

Peripheral myeloid cells contribute to brain injury in male neonatal mice

Peripheral myeloid cells contribute to brain injury in male neonatal mice

Sex-Mediated Differences in LPS Induced Alterations of TNFα, IL-10 Expression, and Prostaglandin Synthesis in Primary Astrocytes

Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

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