Sex-dependent production of eicosanoids in inflammation

Abstract

Eicosanoids (leukotrienes and prostaglandins) are lipid mediators produced from arachidonic acid (AA) involved in several sex-biased immune and inflammatory disorders (i.e. asthma, ulcerative colitis, gout). On the basis of the existent sex difference in leukotriene (LT) biosynthesis in human immune cells (neutrophils and monocytes) due to androgen down-regulation of 5 lipoxygenase (5-LO) product formation, in the present thesis has been investigated the presence of a sex difference in LT biosynthesis as well as the inflammatory reaction in an in vivo model of acute inflammation where LTs play a pivotal role (zymosan-induced peritonitis in mice). After zymosan injection, higher vascular permeability and cell afflux in the peritoneal cavity has been observed in female mice accompanied by higher LT levels in the peritoneal exudates. Interestingly, orchidectomy has been able to induce an increase of LT formation in the exudate of operated mice compared to the sham one. On the cellular level (resident peritoneal macrophages) this sex difference has been related to a differential compartmentalization of 5-LO that leads to a lower production of LTs in male. Intriguingly, no sex differences have been observed in prostaglandin (PG) biosynthesis in the early phase of the inflammatory response after zymosan injection sustained by resident peritoneal macrophages (PM), whether an higher production in PGE2 has been observed in male exudates in the late phase of the inflammatory response, mostly sustained by neutrophils, as confirmed by myeloperoxidase levels. Notably, in another model of acute inflammation such as carrageenan-induced pleurisy in rats, the same events have been observed. In fact, after carrageenan injection, higher production of PGE2 has been found in male pleural exudates in the late times of inflammation when it is supported by neutrophils. Intriguingly, human neutrophils from male have been able to synthesize higher amount of PGE2 compared to female upon in vitro stimulation. This sex difference has been related to the already shown diverse metabolization of AA by 5-LO enzyme, being the production of LT higher in female than in male. In fact, the blockage of 5-LO activity by Mk886 has been able to abolish the sex difference. Intriguingly, this conclusion has been supported by the in vivo abolishment of the sex difference in PGE2 biosynthesis in rats after pre-treatment with Mk886 in the pleurisy model. The results of this thesis clearly demonstrate that sex is an important factor that influences inflammation independently from the stimuli or species.