Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

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

doi:10.1038/s41598-017-03696-8

Simona Pace, Christina Weinigel + Show 8 more

Open Access

https://doi.org/10.1038/s41598-017-03696-8

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Abstract

The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4–8 hrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE2 than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response.

Highlights

Sex has emerged as contributing factor in the incidence and progression of diseases associated with the immune system, in particular inflammation, with implications for outcomes and therapies
We recently reported about a sex-dimorphism in LT biosynthesis[4,5,6] which is of relevance in the light of the well-known sex-biased incidence of several immune diseases, providing a link to asthma pathology in humans[7]
We have previously demonstrated that LT formation in zymosan-induced peritonitis in mice is higher in females compared to males, seemingly due to a divergent subcellular localization of 5-LO in LT-producing peritoneal macrophages[6]

Summary

Introduction

Sex has emerged as contributing factor in the incidence and progression of diseases associated with the immune system, in particular inflammation, with implications for outcomes and therapies. Androgens exert inhibitory effects on LT formation in human innate immune cells (isolated neutrophils or monocytes, and human whole blood) resulting in a substantial lower LT formation in male cells compared to females[4, 5] We recently confirmed these sex differences in vivo, making use of a well-established model of acute inflammation, the zymosan-induced peritonitis in mice[6]. LTs and PGs are locally acting bioactive lipid mediators derived from arachidonic acid (AA) produced by 5-LO and cyclooxygenase (COX) as key enzymes, respectively They are markedly biosynthesized by monocytes/ macrophages, neutrophils, and mast cells and regulate a diverse set of homeostatic and inflammatory processes[8]. Higher PG levels in males are seemingly caused by (i) increased COX-2 expression connected to elevated NF-κB activation versus females and (ii) by AA shunting phenomena due to lower LT production in males

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